Process for activating immune cells

Abstract

The invention relates to methods for activating professional antigen presenting cells and immune cells.

Description

[0001]Process for activating immune cells Field of the invention The invention relates to methods for activating professional antigen presenting cells and immune cells. Background of the invention In recent years CD8 T cells have gained increasing recognition as a key player in disease control, particularly in cancer, but also for infection and autoimmunity. This has motivated a large number of clinical trials and recent approval of new therapies involving T- cell-based or T-cell activating products. Prominent examples of cell-based therapies in clinical development include chimeric antigen-receptor (CAR) T cells, tumour-infiltrating lymphocytes (TILS), T-cell receptor (TCR) therapies or vaccines based on the T cell- activating dendritic cells (Olivera et al. Immuno-Oncology and Technology 24 (2024): 100715). In addition, in biomedical research, effector T cell clones responsive to molecules such as viral proteins or tumour antigens (tumour-specific peptides), are currently commercially available and paramount to preclinical and basic research centered on human adaptive immune responses. Common to the production of all such T cells for commercial products are steps that involve their expansion and activation in the laboratory, where the expansion phase occupies a significant amount of the production time though it need not be antigen specific (Selvarajan et al. Frontiers in Cell and Developmental Biology 12 (2024): 1427171; Wölfl, M. & Greenberg, P.D. Nature Protocols 9, 950-966 (2014); Ghaffari, S. et al. BMC Immunology 22, 43 (2021)). In the case where antigen-specific T cells are desired to be grown from a pool of naïve, unmodified primary T cells, stimulation with antigen-loaded monocyte-derived dendritic cells (DCs) is a gold standard benchmark for their production (Hont et al. Molecular Therapy 30.6 (2022): 2130-2152.; Wölfl, M. & Greenberg, P.D. Nature Protocols 9, 950-966 (2014); Ghaffari, S. et al. BMC Immunology 22, 43 (2021)). Through a process termed antigen cross-presentation, DCs activate CD8+ T cells by providing 3 signals: signal 1, a peptide antigen presented in the context of Class I HLA (MHC-I) molecules that is recognized directly by the TCR; signal 2 in the form of membrane- bound co-stimulatory molecules whose ligation is required to reinforce TCR signaling; and signal 3 in the form of soluble mitogenic cytokines. In the most common procedures, T cells are expanded with a combination of anti-CD3 which clusters TCR and provides an antigen- independent stimulus for signal 1; anti-CD28 antibodies as a surrogate signal 2; and IL-2 supplementation in the media as signal 3 (Ghaffari, S. et al. BMC Immunology 22, 43 (2021); Selvarajan et al. Frontiers in Cell and Developmental Biology 12 (2024): 1427171). Successfully activated T cells will themselves produce more IL-2 and this cytokine’s presence in the supernatant of DC:T-cell cross-presentation co-cultures is often used as an indicator of increased T-cell proliferation. Alternatively, and particularly when measuring cross- presentation in human cells, the production of interferon gamma (IFNγ, IFNG) is used as an indicator of successful T cell activation and polarization towards a cytotoxic phenotype, and as such is a correlate of the combined quantity and quality of T cell activation (Selvarajan et al. Frontiers in Cell and Developmental Biology 12 (2024): 1427171). A myriad of methods of expanding and activating T cells have been published. They often include a series of activation and rest periods that induce the proliferation and in some cases differentiation of the T cells into antigen-specific clones. This involves culturing with cytokines such as (non-exhaustive list): IL-2, insulin, IFNG, GM-CSF, IL-10, TNF, TGF, IL- 7 and IL-15, stimulation with the mitogen phytohemagglutinin (PHA), calcium ionophore A23187, phorbol 12-myristate 13-acetate (PMA), or contact with a protein kinase C activator (e.g., bryostatin) in conjunction with a calcium ionophore stimulation. Other additives include surfactant, plasmanate, and reducing agents such as N-acetyl-cysteine and 2-mercaptoethanol. In addition, co-culture with irradiated peripheral blood mononuclear cells (PBMCs, including monocytes, macrophages or circulating DCs) or other natural or artificial antigen presenting cells, stimulation with antigenic peptides (for antigen-specific clones), and / or stimulation with CD3 / CD28 beads that provide a proliferation and co-stimulatory signal may be included in the expansion / activation protocol. An expansion period may take from weeks to months. It is an object of the invention to develop new methods to reduce the expansion activation cycle delay when activating immune cells and to improve the quality of the resulting immune cells. Summary of the invention The present inventors surprisingly found that modulators of the store-operated calcium entry (SOCE) pathway are capable of improving the presentation of exogenous antigen by antigen presenting cells (APCs). The APCs were used to activate immune cells, and particularly improve the activation and expansion of antigen-specific T cells, thus reducing the activation / expansion cycle delay suffered by traditional methods and improving the quality of the T cells produced. The treated APCs themselves were also demonstrated to improve the efficacy of a dendritic cell vaccine. Improved activation of immune cells was also achieved via contacting the immune cells directly with the SOCE modulator. Accordingly, the invention provides a method of promoting antigen presentation in a professional antigen presenting cell (APC), comprising contacting the professional APC with an antigen and a modulator of store-operated calcium entry (SOCE). The invention also provides a method of activating an immune cell, wherein the method comprises performing the method of promoting antigen presentation to thereby produce an antigen-loaded professional APC, and contacting the antigen-loaded professional APC with the immune cell. The invention further provides a method of activating a population of T cells specific for an antigen, wherein the method comprises performing the method of promoting antigen presentation to thereby produce an antigen-loaded professional APC, and contacting the antigen-loaded professional APC with a population of T cells. The invention also provides a method of activating an immune cell, wherein the method comprises contacting the immune cell with a modulator of store-operated calcium entry (SOCE), wherein the modulator of SOCE is 2-aminoethyl diphenylborinate (2APB) or a derivative thereof. The invention also relates to a professional APC obtained or obtainable by a method of the invention, an immune cell obtained or obtainable by a method of the invention, or a population of T cells obtained or obtainable by a method of the invention. The invention also provides a pharmaceutical composition comprising a professional APC obtained or obtainable by a method of the invention, an immune cell obtained or obtainable by a method of the invention, or a population of T cells obtained or obtainable by a method of the invention. The invention also provides therapeutic uses of the pharmaceutical composition. For example, the invention provides the pharmaceutical composition of the invention for use in a method of treating a disease in a subject. The invention further provides a use of a modulator of store-operated calcium entry (SOCE) for promoting antigen presentation in a professional APC. The invention also provides the compounds p-I-2APB in open form, bis-m-Br-2APB, bis-1,3-2APB in closed form, bis-1,4-2APB in closed form, and 2-aminohexadecanoic acid-p- Br-2APB. Brief description of the figures Figure 1. SOCE-modulating drugs boost murine DCs cross-presentation. A) Irradiated lipopolysaccharide (LPS)-matured bone-marrow derived dendritic cells (BMDCs) treated with the known SOCE activator drug thapsigargin (Tg), or dimethyl sulfoxide (DMSO) as vehicle control, and exposed to ovalbumin (OVA)-coated beads (OVAb) enhance the proliferation of naïve OT-1 CD8 T cells compared to untreated controls, measured by BrdU incorporation (values normalized to control). B) Confirmation of the T cell activation enhancement by the application of Tg to DCs, using indicated cell line / primary cell DC:T cell combinations and different antigen formats, including OVAb, soluble long ovalbumin-derived peptide OT-I-L, and tumor lysates (Tlys) prepared from B16-melanoma cells expressing ovalbumin. C) Screening of various chemicals, including new analogs of the known SOCE modulator 2-Aminoethoxydiphenyl borate (2APB), using the DC cell line JAWSII, LPS- matured, pulsed with OVAb, and co-cultured with the CD8 T cell hybridoma B3Z, identifying Tg and pBr as enhancers of T cell activation, measured as IL-2 production by ELISA. D) The structure of 2APB and its analog para-bromo-2APB (p-Br-2APB; also abbreviated as pBr herein), published in Schild et al 2020. E-F) OVAb-loaded BMDCs treated with the specified concentration of Tg or pBr (pBr / Tg concentrations shown in the graph, in µM), DMSO- vehicle control or no drug (CTR), co-cultured with OT-1 CD8 T cells. Cross-presentation measured as 24h levels of (E) IL-2 and (F) IFNG production show a bell-shaped stimulation. (n=3) G-I) Confirmation of the T cell activation enhancement by the application of Tg and pBr to DCs, using BMDCs:OT-1 DC:T cell combinations, ratio 1:2, and different antigen formats, including OVAb, OT-I-L, and Tlys, measured by (G) IL-2, (H) IFNG production, or (I) proliferation. Bars are means + SEM. Each dot in the bar graphs represents a biological replicate. All data is normalized by experimental day. Significant p-values (calculated using unpaired t-test, One or Two-way ANOVA with Sidak or Dunnet’s post-hoc test) are *0.01- 0.05, **0.001-0.01, ***<0.001 or shown above bars. CPA, cyclopiazonic acid; PAF, Platelet activator factor; 2APB analogs are named according to the position (para- ortho- meta-) and element of the modification with respect to 2APB parental molecule: p-Br, para-bromo- 2APB; o-Cl, ortho-chloro-2APB; p-F, para-fluoro-2APB; o-Br, ortho-bromo-2APB; Trp, L-5- hydroxytryptophan-2APB; o-F, ortho-fluoro-2APB; p-SO2, (p-SO2NMe2) para- dimethylsulfamoyl-2APB; m-F, meta-fluoro-2APB; Met, L-methionine-2APB. Figure 2. Additional modulators boosting DCs cross-presentation. A) Following the same procedure as in Figure 1B-C, results showed up to 6-fold increase in B3Z T cell activation measured by IL-2 production after 24h co-culture with JAWSII or BMDCs, previously exposed to OVAb or Tlys and treated with the ceramide-producing SOCE stimulator molecule palmitate (BSA-Palm; concentrations in µM) versus BSA vehicle control. B) Dose-response (24h IL-2 production) of OVAb-loaded BMDCs treated with the specified concentration of BSA-Palm (µM) or BSA vehicle control, co-cultured with B3Z CD8 T cells. C-D) Dose-response of OVAb-loaded BMDCs treated with the specified concentration of a new 2APB-analog, para-Iodine (p-I) (concentrations in µM), DMSO vehicle control, or no drug control (CTR), co-cultured with OT-1 CD8 T cells. T cell activation measured by IL-2 (C) or IFNG (D) production after 24h co-culture (n=2-3). E) Chemicals screened in Figure 1C were re-evaluated using a similar protocol but with different concentrations (within brackets in µM). Improved cross-presentation was observed only at specific doses for certain compounds indicating the importance of optimizing concentration to induce a strong DC- boosting effect. Bars are means + SEM. Each dot in the bar graphs represents a biological replicate. All data are normalized by experimental day. Significant p-values (calculated using Two-way ANOVA with Sidak post-hoc test) are *0.01-0.05, **0.001-0.01, ***<0.001. Figure 3. SOCE-modulators preserve BMDCs viability and migration capacity. A) LPS-matured BMDCs loaded with OVAb or no antigen (CTR) were incubated for 4h with SOCE-modulating drugs at the concentrations indicated in the graph (in µM), or with Triton detergent (TX) as a positive control of toxicity. Resazurin reduction assay was used to evaluate the relative viability. No significant decrease in viability was observed after SOCE- treatment. Values are normalized by the average values of each experiment. B) LPS-matured BMDCs unloaded (n=2-3) or loaded with OVAb (n=1) were treated for 4h with SOCE modulators, then transferred to transwells. Directional migration towards the specific chemokine CCL21 (or no CCL21 as a negative control of migration) was evaluated after 24h by cell numbers measurement by flow cytometry. SOCE-treatment does not affect migration in vitro. Values are normalized by total number of cells per day. C) Evaluation of in vivo migration of SOCE-treated carboxyfluorescein-succinimidyl ester (CFSE)-labeled CD45.1 BMDCs, as measured by %CFSE+ cells after 24h in draining popliteal lymph nodes of CD45.2 recipient mice, showed a non-significant impact of SOCE-treatment, although a trend for reduced migration of Tg-treated unloaded (but not OT-I-L antigen-loaded) BMDCs was observed. Bars are means + SEM. Each dot in the bar graphs represents a biological replicate. Significance was calculated using One or Two-way ANOVA with Dunnet’s post-hoc test, #= significant to all conditions (except TX with each other in A). Figure 4. SOCE-modulators enhance in vivo BMDCs cross-presentation. A) CD45.2 mice received intravenous CFSE-labeled OT-1 CD8+ T cells followed by footpad vaccination (DCVAC) with LPS-matured BMDCs loaded with OT-I-L or no antigen (CTR) and treated with SOCE-modulating drugs Tg or pBr, or DMSO vehicle control. DCVAC- induced proliferation of OT-1 cells was observed by increased numbers specifically in draining lymph nodes (dLN) but not contralateral LN (CtrlLN). pBr treatment further significantly increased OT-1 proliferation only in the dLN of mice vaccinated with antigen- loaded BMDCs. B) Proliferation, measured as decreased CFSE Geometric mean fluorescence (GeoMFI) of OT-1 cells within the dLN, was significantly increased by SOCE-treated antigen-loaded DCVAC (OTIL), but not with unloaded-DCVAC (CTR). C) Tg-treated unloaded-DCVAC induces a small antigen-unspecific activation of OT-1 cells measured by increased CD25+CD69+ surface expression, whereas activation is not different in antigen- loaded cells, suggesting excessive activation is likely not induced in the absence of T cell targets. Bars are means + SEM. Each dot in the bar graphs represents a biological replicate. Significant p-values calculated using One or Two-way ANOVA with Dunnet’s post-hoc test are shown above bars, except in A) in which all CtrlLN conditions were significant but p values are not shown. Figure 5. Intracellular calcium signaling induced by Tg and pBr drug treatment. A) Fluo-8 loaded BMDCs were treated with either Tg or pBr at the concentrations shown in the graph (in µM), in calcium-containing medium. Black arrow indicates drug addition. DMSO at the highest concentration used among the other drugs, or no drug (CTR) were used as controls. Fluorescence values (F) were normalized by the average well fluorescence during 1 min prior to drug addition (F0), normalized ratio (F / F0) is shown. Quantification of maximum peak values (ΔPeak) of the curves are shown in the bar graph below calcium traces. Total calcium signal, comparable between drugs, is significantly increased with respect to control. B) Pre-treatment of BMDCs with Orai inhibitor GSK-7975A (GSK) prior to SOCE- drug treatment, abrogated drug-induced calcium signaling, demonstrating the involvement of the Orai channels. C) Similar to B, pre-treatment of BMDCs with IP3 receptor (IP3R) inhibitor Xestospongin C prior to SOCE-drug treatment, abolished the significant increase in calcium signaling demonstrating the involvement of the IP3R. D) Fluo-8 loaded BMDCs were pre-exposed to calcium-free media (CF) by addition of 2 mM EGTA. Cells were then treated as in A. Increased in cytosolic calcium indicates calcium release from intracellular stores. Area under the curve (AUC) values of F / F0 curves are shown below as an indication of endoplasmic reticulum (ER) calcium release. Both drugs show similar levels of significant ER depletion, except for a lower trend of pBr at 5 µM, although the difference between this condition and the other drug treatments was not significant. E) After drug treatment shown in D, additional calcium was added to the extracellular milieu. Increased cytosolic calcium indicates calcium influx (SOCE). Maximum peak values of F / F0 curves are shown below as a measurement of SOCE. Bars are means + / - SEM. Each dot in the bar graphs represents a biological replicate. Significant p-values calculated using One-way ANOVA with Tukey’s post-hoc test are shown above bars. Figure 6. Mechanistic insights into the enhancing effect of SOCE-modulating drugs on murine DC-mediated T cell responses. LPS-matured BMDCs were loaded with various antigen formats of the OVA model antigen: soluble OT-I-L or SIINFEKL (OT-I) peptides, particulate OVAb, or lysate of B16-OVA tumor cells (Tlys), or their respective controls: no antigen (CTR) or uncoupled beads (CTRb), and treated with SOCE-modulators Tg or pBr, or no treatment (CTR) or DMSO vehicle control for 4h. Antigen format is specified in each figure. Tg was used at 0.1 µM and pBr at 10 µM, unless otherwise specified. A) Flow cytometry analysis of MHC-I-peptide complex on the surface of BMDCs showed no differences among treatments. OVAb showed no signal above CTRb. B) Immunofluorescence analysis of OVA levels after 4h phagocytosis of OVAb revealed decreased antigen (Ag) degradation (higher antigen remaining) in Tg-treated BMDCs but not pBr. Significant p- values calculated using One or Two-way ANOVA with Dunnet’s post-hoc test are shown above bars. C) Flow cytometry analysis of the activation marker CD86 on the surface of BMDCs showed no differences among treatments. D) Flow cytometry analysis of MHC-II on the surface of BMDCs showed no differences among treatments. E) Supernatant evaluation of secreted IL-12p70 by ELISA showed no differences among conditions tested. F) Cytokine array screening revealed increased ICAM-1, CXCL13 and CXCL11. Bars are means + SEM. Each dot in the bar graphs represents a biological replicate (mouse), with the exception of the cytokine array, where mixture of supernatants gathered from 3 mice were assayed in two replicates. Figure 7. SOCE-modulating drugs boost human DCs cross-presentation. Matured human monocyte-derived DCs (MoDCs), loaded with soluble Melan-A / MART-1 long (MLANA-L) peptide and treated with SOCE modulators Tg, pBr and pI (concentrations shown in graphs, in µM), enhance the activation of both (A-D) Melan-A specific CD8+ T cell clones and (E-H) allogeneic naïve T cells after 24, 48 or 72h co-culture. A) Treatment with Tg, but not pBr, increased IL-2 production by T cell clones at 24, 48 and 72h co-culture, compared to controls (CTR). B) Both Tg and pBr treatment increase IFNG production by T cell clones at 24 and 48h. At 72h, Tg (0.1 µM but not 0.05 µM), but not pBr, further increases IFNG production by T cell clones, also showing potential antigen-unspecific effects (that could also arise from HLA mismatches). C) Both Tg and pBr treatments enhance proliferation of T cell clones in an antigen-specific manner, measured by BrdU incorporation. D) Preliminary data with two additional donors indicates pI also enhances IFNG production after 72h. E) Treatment with both Tg and pBr increase IL-2 production of allogeneic naïve T cells at 24 and 48h, where Tg starts showing potential antigen-unspecific effects. At 72h, Tg, but not pBr, further increases IL-2 production by naïve T cells, also showing potential antigen- unspecific effects (that could also arise from HLA mismatches. F) IFNG production by naïve T cells is nearly absent at 24h co-culture, and increases at 48 and 72h, indicating cell activation and polarization. Treatment with Tg, but not pBr, significantly increases polarization, in an antigen-specific (48h) and potentially unspecific (72h) manner. G) Proliferation of naïve cells is MLANA-L antigen-independent, potentially due to the presence of allogeneic antigens (HLA mismatch) masking the specific response, and increased by Tg and pBr treatment. H) Preliminary data with two additional donors indicates pI also shows a trend for increased IFNG production after 72h. Bars are means + SEM. Each dot in the bar graphs represents a biological replicate (MoDC donors). All data is normalized by donor. Significant p-values (calculated using Two-way ANOVA with Dunnet’s post-hoc test, except F) in which each comparison stands alone in order to mitigate the masking effects) are shown above bars. Figure 8. SOCE-modulators enhance the efficacy of anti-melanoma DC-vaccine loaded with OT-I-L soluble peptide. WT C57BL / 6J mice were subcutaneously injected with B16-OVA tumor cells and tumor growth was monitored blindly for 19 days or until tumors from any group reached 15 mm diameter. A) Mice received 2 doses of DC-vaccine (DCVAC) consisting on LPS-matured BMDCs loaded with OT-I-L peptide and treated with SOCE- modulators Tg and pBr, or DMSO as control. Control unvaccinated mice received only a PBS injection (no cells). First vaccination was done at average tumor surface 20-25 mm2and the second 7 days after (indicated by arrows). Vaccination with SOCE-treated BMDCs improves tumor control (n=6-7 per group). Tumors, popliteal lymph nodes (pLN, vaccination draining) and inguinal lymph nodes (iLN, tumor draining) were harvested at the experiment endpoint. B) Tumor weight at the end of the experiment was significantly decreased by pBr treatment. C) Flow cytometry analysis of tumors harvested at the endpoint showed SOCE-modulator treatment significantly increases the proportion of leukocyte infiltration, measured as % CD45+ cells. D) The fraction of total CD8 T cells decreased in the pLN in the Tg group, and remained the same in iLN and tumor across all groups. E) (i) IFNG and (ii) TNFa cytokine production by CD8 T cells is increased only in Tg and pBr-treated conditions in pLN, and in all vaccinated conditions in iLN, but IFNG+ cells are increased in the tumor only in pBr- treated mice. (iii) The trend for increased granzyme B (GrzB) production intratumorally in SOCE-modulator treated conditions was not significant, although (iv) the density of GrzB- producing cells was increased in the tumors of pBr-treated mice compared to control. F) The proportion of CD4 Th cells (FoxP3-) are increased intra-tumorally in Tg-treated DC-vaccine groups. G) pBr-DCVAC increases intra-tumoral IFNG+ CD4 T cells, indicative of a Th1 CD4 subset induction, and (ii) Tg and pBr-treated conditions increase TNFa+ CD4 T cells in the pLN, and all vaccinated conditions in iLN but not in the tumor, indicating a potential induction of Th1 and / or Th17 CD4 subset. H) (i) No significant changes in the proportion of Tregs (CD4+FoxP3+) within the tumor is observed although increased Tregs in the pLN of DMSO condition was noted. Tg-and pBr-treated vaccination increased the ratio of (ii) CD8 T cells, but not (iii) CD4 Th to Tregs ratios. I) Although only slight global changes were noted in (i) the percentage of total DCs (CD11c+MHC-II+) in the pLN and tumors of DMSO and Tg-treated groups, treatment-depended changes in the DC subsets MoDCs (Ly6C+), cDC1 (XCR1+) and cDC2 (CD11b+) populations were noted. This included (ii) increased fraction of tumor MoDCs in Tg-DCVAC; (iii) decrease in total cDC1 in pLN although accompanied by (iv) an increased fraction of proliferating cDC1s in pLN with Tg and pBr and in tumors with pBr; and finally (v) increased total cDC2s in tumors of the pBr group. Bars are means + SEM. Each dot in the bar graphs represents a biological replicate (mouse). Significant p- values calculated using One or Two-way ANOVA with Dunnet’s post-hoc test are shown above bars. Figure 9 (Supplementary data related to Figure 8). SOCE modulators enhance the efficacy of an anti-melanoma DC-vaccine loaded with OT-I-L soluble peptide. A) The trends for increased tumor density of (i) total CD8 and (ii) IFNG+ CD8 cells in SOCE-treated groups, and (iii) decreased tumor density of TNFa+ CD8 cells in DMSO and Tg but not pBr groups were not significant. B) The trends for increased intratumoral density of (i) total CD4 Th cells, (ii) IFNG+ or (iii) TNFa+ CD4 T cells were not significant. C) (i) Intratumoral density of Tregs was not changed among groups, though a slight trend for an increase was noted in the pBr group, and (ii) Tregs proliferation was increased in the pLN of SOCE-treated vaccinated groups. Bars are means + SEM. Each dot in the bar graphs represents a biological replicate (mouse). Significant p-values calculated using One or Two-way ANOVA with Dunnet’s post-hoc test are shown above bars. Figure 10. SOCE-modulators enhance the efficacy of an anti-melanoma DC- vaccine loaded with a lysate of melanoma tumor cells. WT C57BL / 6J mice were subcutaneously injected with B16-OVA tumor cells and tumor growth was monitored blindly for 19 days or until tumors reached 15 mm diameter. A) Mice received 2 doses of DC- vaccine (DCVAC) consisting on LPS-matured BMDCs loaded with a lysate of B16-OVA tumor cells (Tlys) and treated with SOCE-modulators Tg and pBr, or DMSO as control. Control unvaccinated mice received only a PBS injection (no cells). First vaccination was done at average tumor surface 20-25 mm2and the second 7 days after (indicated by arrows in A). Tumors, pLN (vaccination draining) and iLN (tumor draining) were harvested at the experiment endpoint. A) Tumor control is significantly improved in Tg and pBr-treated groups compared to both PBS as well as DMSO controls (n=13-15 mice). B) (i) Endpoint tumor weight is significantly decreased in Tg and pBr-treated groups, and (ii) the proliferation of tumor-associated (CD45-) cells is decreased in DMSO and Tg groups. C) Leukocyte (i) proportion and (ii) density is increased after vaccination with SOCE-treated BMDCs, where density is also significantly increased as compared to DMSO. D) CD8 T cell (i) density and (ii) proliferation is increased intra-tumorally in SOCE-treated groups, where pBr induced additional improvement over DMSO. E) CD4 Th cells (i) density and (ii) proliferation is increased intra-tumorally in all vaccinated groups where pBr induced further improvement over (i) DMSO and (ii) Tg. In the DMSO-treated group CD4 T cells were also augmented in the pLN. F) Vaccination does not affect (i) density or (ii) proliferation of Tregs. G) CD8 T cell (i, ii) cytokine (IFNG, TNFa) and (iii) GrzB production is increased intra-tumorally after DC-vaccine and further increased in SOCE-treated groups, and it is mostly absent in pLN and iLN, indicating cytotoxic activity within the tumor. (iv-v) Exhaustion of CD8 T cells is partially increased in the tumor of pBr-treated (LAG3+PD1+, but not TIM3+PD1+) groups. H) (i) IFNG cytokine production by CD4 T cells (associated with Th1 subset) is increased in the pLN of the DMSO group and unchanged otherwise after vaccination while (ii) TNFa (associated with both Th2 / Th17 phenotypes) is increased in the Tg group in the pLN and in the pBr group in the iLN, with a concomitant decrease in tumors of the DMSO and pBr groups, whereas the (iii) tumor density of TNFa+CD4+ cells is increased only in the Tg group. (iv) The fraction of Th2 CD4 T cells (IL-4+) is decreased in DMSO but not SOCE- treated groups while (v) the proportion of Th17 (IL-17A+) cells are unchanged in tumors, whereas the (vi) tumor density of IL-17A+ cells is increased in the pBr group. I) The percentage of (i) natural killer (NK, TCR-NKP46+) cells was increased in tumors by vaccination and further significantly increased in both SOCE-treated groups with respect to DMSO, whereas the (ii) tumor density of NK cells was significantly increased only in the pBr group. (iii) The fraction of proliferating NK cells was increased in both Tg and pBr groups, whereas the fractions of (iv) cytotoxic (GrzB+) and (v) IFNG+ NK cells were increased only in the pBr group. J) Although the percentage of (i) total B cells (CD19+) in tumors was generally decreased by vaccination, the (ii) tumor B cell density was unchanged, and (iii) the fraction of B cells displaying activation markers (CD80+ MHC-II+) was increased in both Tg and pBr, where the Tg group was further significantly increased compared to the DMSO group. K) Although the fraction of (i) total tumor infiltrating DCs was unchanged, the (ii) tumor density of DCs was increased in both SOCE-treated groups with the pBr group displaying a further increase with respect to the DMSO group. L) A similar pattern for both the fraction (i) and (ii) and density was observed for total tumor macrophages (Mφ, F4 / 80+), and particularly the (iii) anti-tumor M1 (iNOS+) phenotype, whereas the fraction of (iv) tumor-promoting M2 (CD206+) phenotype was significantly decreased in both SOCE-treated groups with respect to DMSO. Bars are means + SEM. Each dot in the bar graphs represents a biological replicate (mouse). Significant p-values calculated using One or Two-way ANOVA with Dunnet’s post-hoc test are shown above bars. Figure 11 (Supplementary data related to Figure 10). SOCE-modulators enhance the efficacy of an anti-melanoma DC-vaccine loaded with a lysate of melanoma tumor cells. A) Mice received 2 doses of DC-vaccine consisting on LPS-matured unloaded (no antigen) BMDCs and treated with SOCE modulators Tg and pBr, or DMSO as control. Control unvaccinated mice received only a PBS injection. First vaccination was done at average tumor surface 20-25 mm2and the second 6 days after (indicated by arrows). Vaccination does not improve, and DMSO- and Tg-treated vaccinated groups worsen tumor control compared to unvaccinated, highlighting the importance of antigen presentation in anti- tumor responses, as well as potential antigen-independent benefits of pBr treatment. (n=6-7 per group) B-F) The percentage of total (B) CD8 T and (C) CD4 Th (FoxP3-) cells remained unchanged in all conditions, whereas vaccination generally decreased the (D) percentage of Tregs (FoxP3+) in tumors. The resulting ratios of (E) CD8:Tregs were significantly increased only in tumors of SOCE-treated groups, whereas the ratios of (F) CD4:Tregs were increased across all vaccinated groups indicating a generally positive immune balance. G) Whereas (i) MoDCs (Ly6C+ DCs(CD11c+MHC-II+)) were increased in the DMSO group only, the fraction of (ii) cDC1s (XCR1+) and (iii) cDC2s (CD11b+) were similar in tumors across all groups. H) (i) Tumor-promoting monocytic myeloid-derived suppressor cells (M-MDSCs: CD11b+Ly6C+Ly6G-) were unchanged across groups, while (ii) tumors of pBr-treated mice showed decreased granulocyte-neutrophil myeloid-derived suppressor cells (PMN-MDSCs: Ly6G+CD11b+) infiltration. Bars are means + SEM. Each dot in the bar graphs represents a biological replicate (mouse). Significant p-values calculated using One or Two-way ANOVA with Dunnet’s post-hoc test are shown above bars. Figure 12. SOCE modulators facilitate the detection of T cells specific for immunogenic antigens. Isolated PBMCs from a healthy donor stimulated (+) or not (-) with an immunogenic antigen (Ag) mixture of CMV, EBV and Flu (CEF) peptide pools. The compounds bis-1,3-2APB in closed form (PM), bis-1,4-2APB in closed form (PP), p-Br- 2APB (pBr) or thapsigargin (Tg) were added after antigen stimulation, at the concentrations (in µM) indicated below the graphs. Cells were stained for lineage and activation markers and analyzed by flow cytometry. (A-B) Percentages of viable cells expressing CD8+ (A) and CD4+ (B) T cell lineage markers and producing IL-2, TNFA or IFNG are shown. (C-D) Mean fluorescence intensity (MFI) of IFNG in CD8+ (B) and CD4+ (D) T cells is shown. Tg induced large increases in the percentages of both antigen-specific and non-specific T cells, while 2-APB derivatives (2-APB deriv.) more consistently boosted antigen-specific cell percentages and signals to varying degrees in a concentration-dependent manner. Figure 13. SOCE modulators facilitate the detection of T cells specific for weakly immunogenic antigens, and promote the growth of antigen-specific T cells. Isolated PBMCs from a healthy donor were stimulated (+) or not (-) with the weakly immunogenic measles NP antigen (Ag) and PM (5 µM), or Tg (0.1 µM). Cells were then stained for lineage and activation markers and analyzed by flow cytometry. (A-B) The percentage of CD8+ (A) and CD4+ (B) T cells producing IL-2, TNFA, IFNG or all 3 cytokines is shown. Tg strongly boosted both antigen-specific and non-specific T cells, especially in CD4⁺ cells, whereas PM preferentially expanded antigen-specific CD8⁺ cells, with a smaller increase in CD4⁺ cells. (C) PMBCs were stimulated (+) or not (-) with a CEF peptide pool (Ag) and PM for 4h, and cultured for 14 days. Fold expansion with respect to the initially seeded cell numbers is shown. The black dotted lines indicate that, in the presence of the PM compound, a fold expansion comparable to that observed at day 14 under control conditions is already achieved by day 7. Detailed Description In a first aspect, the invention relates to a method of promoting antigen presentation by an antigen presenting cell (APC). The method comprises contacting the APC with an antigen and a modulator of store-operated calcium entry (SOCE). The APC is typically a professional APC. In some cases, the method may be for promoting antigen cross-presentation in the APC. For example, the method may be for promoting antigen cross-presentation in a professional APC. The inventors have surprisingly found that the functions of an APC for enhancing an immune response can be improved when contacting the APC with an exogenous antigen and a modulator of SOCE. This has a downstream effect of increasing the activation of antigen- specific immune cells, such as CD8+T cells, CD4+T cells and B cells, as well as immune cells that are not antigen specific such as macrophages, mast cells, natural killer cells and dendritic cells. Antigen presentation may be increased by at least 10% when compared to an otherwise identical method that does not involve the modulator of SOCE. For example, antigen presentation may be increased by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200% or at least 300% when compared to an otherwise identical method that does not involve the modulator of SOCE. Similarly, antigen cross-presentation may be increased by at least 10% when compared to an otherwise identical method that does not involve the modulator of SOCE. For example, antigen cross-presentation may be increased by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200% or at least 300% when compared to an otherwise identical method that does not involve the modulator of SOCE. An increase in antigen presentation, such as antigen cross-presentation may be calculated by maturing human monocyte-derived dendritic cells for 16 hours with a dendritic cell (DC) maturation cocktail (20 ng / ml TNFα, 15 ng / mL IL-6 and 5ng / mL IL-1β), followed by addition of an antigen (such as 10µM MLANA16-40(A27L)dissolved in DMSO) for 10 minutes, followed by the addition of the modulator of SOCE (solubilised in DMSO) or a DMSO vehicle, incubation of the DCs for a further 4 hours, washing twice of the DCs in complete medium, and addition of T cells added at a ratio of 2:1 to DCs, incubated at 37˚C, 5% CO2and supernatant collected at 24, 48 and 72 hours. The greatest increase in the levels of IL-2 cytokine in the supernatant corresponds to increased cross-presentation. The T cells may be a human antigen-specific effector CD8 T cell clone (grown from a single cell), or a 1:1 mixture of total circulating primary naïve CD4 and CD8 T cells. Also provided is a method of promoting activation of an antigen presenting cell (APC). The method comprises contacting the APC with an antigen and a modulator of store-operated calcium entry (SOCE). The APC is typically a professional APC. Activation of the APC may be increased by at least 10% when compared to an otherwise identical method that does not involve the modulator of SOCE. For example, activation of the APC may be increased by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200% or at least 300% when compared to an otherwise identical method that does not involve the modulator of SOCE. An increase in the activation of the APC may be calculated based on the resulting activation of T cells activated by the APC. For example, an increase in the activation of the APC may be calculated by maturing human monocyte-derived dendritic cells for 16 hours with a dendritic cell (DC) maturation cocktail (20 ng / ml TNFα, 15 ng / mL IL-6 and 5ng / mL IL-1β), followed by addition of an antigen (such as 10µM MLANA16-40(A27L) dissolved in DMSO) for 10 minutes, followed by the addition of the modulator of SOCE (solubilised in DMSO) or a DMSO vehicle, incubation of the DCs for a further 4 hours, washing twice of the DCs in complete medium, and addition of T cells added at a ratio of 2:1 to DCs, incubated at 37˚C, 5% CO2and supernatant collected at 24, 48 and 72 hours. The greatest increase in the levels of IL-2 cytokine in the supernatant corresponds to increased cross-presentation. The T cells may be a human antigen-specific effector CD8 T cell clone (grown from a single cell), or a 1:1 mixture of total circulating primary naïve CD4 and CD8 T cells. The APC may be contacted with the antigen before, after or simultaneously with the modulator of SOCE. Preferably, the APC is contacted with the antigen before it is contacted with the modulator of SOCE. For example, the APC may be contacted with the antigen at least 1 minute before it is contacted with the modulator of SOCE, such as at least 2 minutes, at least 5 minutes or at least 10 minutes before it is contacted with the modulator of SOCE. The APC may be contacted with the antigen at most 120 minutes after it is contacted with the modulator of SOCE, such as at most 60 minutes, 30 minutes, 20 minutes or 15 minutes before it is contacted with the modulator of SOCE. The APC may be contacted with the antigen about 10 minutes before it is contacted with the modulator of SOCE. The APC may be contacted with the antigen 1-120 minutes before it is contacted with the modulator of SOCE, such as 1-60 minutes, 1-30 minutes, 1-20 minutes, 1-15 minutes, 2-120 minutes, 2-60 minutes, 2-30 minutes, 2-20 minutes, 2-15 minutes, 5-120 minutes, 5-60 minutes, 5-30 minutes, 5-20 minutes or 5-15 minutes before it is contacted with the modulator of SOCE. Preferably, the APC is contacted with the antigen 5-30 minutes before it is contacted with the modulator of SOCE. The APC may be contacted with the antigen about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes or about 30 minutes before it is contacted with the modulator of SOCE, preferably about 10 minutes before it is contacted with the modulator of SOCE. The inventors identified that contacting the APC with the antigen concomitantly or after the modulator of SOCE may result in reduced antigen uptake when compared to levels of antigen uptake achieved when antigen is contacted with the APC before contact with the modulator of SOCE. The step of contacting the APC with an antigen and a modulator of SOCE may be performed in the absence of CD8+T cells. The step of contacting the APC with an antigen and a modulator of SOCE may be performed in the absence of CD8+and CD4+T cells. The step of contacting the APC with an antigen and a modulator of SOCE may be performed in the absence T cells. The step of contacting the APC with an antigen and a modulator of SOCE may be performed in the absence of T cells, B cells, macrophages, natural killer (NK cells) and mast cells. The step of contacting the APC with an antigen and a modulator of SOCE may be performed in the absence of immune effector cells other than the APC. Alternatively, the steps of contacting the APC with an antigen and / or contacting the APC with a modulator of SOCE may be performed in the presence of CD8+and CD4+T cells. The steps of contacting the APC with an antigen and / or contacting the APC with a modulator of SOCE may be performed in the presence of immune cells. In other words, provided herein is a method for promoting antigen presentation in an APC, such as a professional APC, comprising contacting a population of cells comprising an APC and an immune cell with an antigen and a modulator of store-operated calcium entry (SOCE). Any suitable population of cells may be used. The population of cells may be peripheral blood mononuclear cells (PBMCs). As demonstrated in Example 7, populations of cells comprising APCs and immune cells, when contacted with an antigen and a SOCE modulator, are capable of achieving antigen-specific immune cell activation that would be otherwise undetectable. Without wishing to be bound by theory, it is hypothesized that increased antigen presentation by the APCs in the population contributes to the increased activation of the immune cells specific for the antigen. The methods may further comprise contacting the APC with a molecule that stimulates ceramide production. The molecule that stimulates ceramide production may comprise a palmitoyl (otherwise known as hexadecenoic acid) moiety. In some cases, the modulator of SOCE comprises the molecule that stimulates ceramide production, such as a palmitoyl moiety. Where the APC is a professional APC, prior to the step of contacting an APC with an antigen and a modulator of SOCE, the methods may comprise maturing the professional APC. Maturation of the APC may be performed through any means known to the skilled person. For example, maturation may be performed by contacting the professional APC with lipopolysaccharide (LPS). The LPS may be used at a concentration of 0.01 μg / ml – 10 μg / ml, such as 0.1 μg / ml to 5 μg / ml, or 0.5 μg / ml to 2 μg / ml. The LPS may be used at a concentration of about 0.1 μg / ml, about 0.5 μg / ml, about 1 μg / ml, about 2 μg / ml or about 5 μg / ml, preferably about 1 μg / ml. Maturation may be performed by contacting the professional APC with TNFα, IL-6 and / or IL-1β. TNFα may be used at a concentration of 5 ng / ml to 50 ng / ml, such as 10 ng / ml to 30 ng / ml, preferably about 20 ng / ml. IL-6 may be used at a concentration of 5 ng / ml to 50 ng / ml, such as 10 ng / ml to 20 ng / ml, preferably about 15 ng / ml. IL-1β may be used at a concentration of 1 ng / ml to 20 ng / ml, such as 2 ng / ml to 10 ng / ml, preferably about 5 ng / ml. Maturation may be performed for at least 4 hours, such as at least 8, 12 or 16 hours. Maturation may be performed for at most 48 hours, such as at most 24, 20 or 16 hours. Maturation may be performed for 4-48 hours, such as 8-24 hours, 12 to 20 hours, or about 16 hours. In some cases, the professional APC to be matured is a dendritic cell. In a second aspect, the invention relates to a method of activating an immune cell. The method comprises contacting the APC, produced according to the method of promoting antigen presentation or to the method of promoting activation, with the immune cell. For example, the method may comprise contacting the antigen-loaded APC or the activated APC, produced according to a method disclosed herein, with the immune cell. The method may comprise contacting the APC with an antigen and a modulator of SOCE, and contacting said APC with the immune cell. The step of contacting the APC with an antigen and a modulator of SOCE may be performed according to any of the aspects described herein. The APC may be contacted with the immune cell before, after or simultaneously with the step of contacting the APC with the antigen and the modulator of SOCE. Preferably, the APC is contacted with the immune cell after the step of contacting the APC with the antigen and the modulator of SOCE. In other words, the immune cell is not present during the step(s) of contacting the APC with the antigen and the modulator of SOCE. For example, the method may comprise contacting the APC with an antigen and a modulator of SOCE, incubating the APC, and contacting said APC with the immune cell. The incubation may be performed for at least 15 minutes, such as at least 30 minutes, at least 1 hour, at least 2 hours or at least 4 hours. The incubation may be performed for at most 24 hours, such as at most 18 hours, at most 12 hours, at most 8 hours, or at most 6 hours. The incubation may be performed for 15 minutes – 24 hours, such as 15 minutes – 18 hours, 15 minutes – 12 hours, 15 minutes – 8 hours, 15 minutes – 6 hours, 30 minutes – 24 hours, 30 minutes – 18 hours, 30 minutes – 12 hours, 30 minutes – 8 hours, 30 minutes – 6 hours, 1-24 hours, 1-18 hours, 1-12 hours, 1-8 hours, 1-6 hours, 2-24 hours, 2-18 hours, 2-12 hours, 2-8 hours, or 2-6 hours. Preferably, the incubation is performed for 1-8 hours, such as 2-6 hours. The incubation may be performed for about 1 hour, 2 hours, 4 hours, 6 hours, 8 hours or 12 hours, preferably for about 4 hours. Accordingly, a method described herein may comprise in order, contacting an APC with an antigen, contacting the APC with a modulator of SOCE, incubating the APC, and contacting the APC with an immune cell. In some instances, the APC may be contacted with the immune cell simultaneously with the step of contacting the APC with the antigen and the modulator of SOCE. In other words, the immune cell is present during the step(s) of contacting the APC with the antigen and the modulator of SOCE. The method may further comprise incubating the APC with the immune cell. In other words, the method may comprise co-culturing the APC with the immune cell. The method may further comprise culturing the immune cell, for example, with or without the APC. The immune cell may be incubated and / or cultured for at least 6 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least 96 hours or at least 120 hours. The immune cell may be incubated and / or cultured for about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours or about 120 hours. Measurements of proliferation have been made at 24h, 48h and 72h after co-culture for murine co-cultures and typically up to 5 or 7 days with human DC:T cell co-cultures. The immune cell may be cultured in the presence the APC. The immune cell may be cultured in the absence of the APC, for example, after an incubation period. In some cases, the method of activating an immune cell is a method of activating a population of T cells specific for an antigen. The method for activating a population of T cells specific for an antigen may comprise contacting the APC, produced according to the method of promoting antigen presentation or to the method of promoting activation, with a population of T cells. For example, the method may comprise contacting an APC with an antigen and a modulator of SOCE, and contacting said APC with a population of T cells. The step of contacting the APC with an antigen and a modulator of SOCE may be performed according to any of the aspects described herein. The step of contacting the APC with a population of T cells may be performed according to any of the aspects described herein with respect to contacting the APC with an immune cell, including any subsequent steps described herein such as incubation or culturing. Without being limited by theory, the present invention is particularly advantageous for activating T cells, such as CD8+T cells, because the enhanced antigen presentation, such as enhanced antigen cross-presentation, leads to the improved activation of T cells expressing a TCR specific for the antigen. The method of activating a population of T cells may further comprise isolating the T cells specific for the antigen. The isolation may be performed by any means known to the skilled person. For example, the isolation may be performed by affinity purification, e.g. using a solid support comprising the antigen and passing the resulting population of T cells. Any suitable solid support comprising the antigen may be used. The antigen may be in the form of an antigen-MHC complex, such as a monomer, tetramer or dextramer. Alternatively, the antigen could be labelled with an affinity tag such as a hexahistidine signal or biotin, and the resulting affinity tag-antigen-T cell complex affinity purified. The isolation may be performed by labelling an antigen fluorescently and selecting labelled cells, e.g. using FACS. Accordingly, a method for activating a population of T cells may comprise contacting an APC with an antigen and a modulator of SOCE, contacting said APC with a population of T cells, culturing the population of T cells, and isolating T cells specific for the antigen. The method of activating a population of T cells may further comprise selecting a T cell clone specific for the antigen, and culturing said clone to produced a clonal population of T cells specific for the antigen. Where the method involves contacting an APC with an immune cell or a population of T cells, the method may further comprise a step of washing the antigen-loaded APC or the activated APC to remove the modulator of SOCE and / or to remove the antigen before contacting the APC with the immune cell or the population of T cells. In a further aspect, a method of activating an immune cell is provided. The method comprises contacting an APC with an antigen and a modulator of SOCE, incubating the APC in a medium, separating the supernatant of the medium from the APC, and contacting the supernatant with the immune cell. The step of contacting the APC with an antigen and a modulator of SOCE may be performed according to any of the aspects described herein. The step of contacting the supernatant with the immune cell may be performed according to any of the aspects described herein with respect to contacting the APC with an immune cell, including any subsequent steps described herein such as incubation or culturing. Without being bound by theory, APCs treated with a modulator of SOCE according to the present disclosure exhibit increased secretion of soluble factors and cytokines such as ICAM-1, CXCL11 and CXCL13, which may contribute to their ability to activate immune cells not only via direct interaction between cell surface molecules, but via soluble factors. The incubation may be performed for at least 15 minutes, such as at least 30 minutes, at least 1 hour, at least 2 hours or at least 4 hours. The incubation may be performed for at most 24 hours, such as at most 18 hours, at most 12 hours, at most 8 hours, or at most 6 hours. The incubation may be performed for 15 minutes – 24 hours, such as 15 minutes – 18 hours, 15 minutes – 12 hours, 15 minutes – 8 hours, 15 minutes – 6 hours, 30 minutes – 24 hours, 30 minutes – 18 hours, 30 minutes – 12 hours, 30 minutes – 8 hours, 30 minutes – 6 hours, 1-24 hours, 1-18 hours, 1-12 hours, 1-8 hours, 1-6 hours, 2-24 hours, 2-18 hours, 2-12 hours, 2-8 hours, or 2-6 hours. Preferably, the incubation is performed for 1-8 hours, such as 2-6 hours. The incubation may be performed for about 1 hour, 2 hours, 4 hours, 6 hours, 8 hours or 12 hours, preferably for about 4 hours. As detailed in Example 7, the modulator of SOCE may, at least partially, activate the immune cell in an antigen-independent manner. Accordingly, provided herein is a method of activating an immune cell, wherein the method comprises contacting the immune cell with a modulator of store-operated calcium entry (SOCE). The modulator of SOCE is typically 2- aminoethyl diphenylborinate (2APB) or a derivative thereof. The derivative of 2APB may be any of the derivatives disclosed herein. The derivative may be bis-1,3-2APB (e.g. in closed form), bis-1,4-2APB (e.g. closed form), as p-Br-2APB or p-I-2APB. The method may be performed in the absence of professional APCs. The method may be performed on an isolated population of the immune cell, for example, on an isolated population of T cells. The method may comprise additional co-stimulatory agents to activate the isolated immune cells, such as the isolated T cells. In other words, the method may comprise an additional co- stimulatory signal that is capable of activating the immune cells. The additional co- stimulatory agent may comprise an anti-CD3 antibody and / or an anti-CD28 antibody. The method may be performed in the absence of an antigen. In some cases, a method of promoting proliferation of an immune cell, or of a population of T cells specific for an antigen, is provided. The method comprises contacting an APC with an antigen and a modulator of SOCE, and contacting the APC with an immune cell or a population of T cells. The step of contacting the APC with an antigen and a modulator of SOCE may be performed according to any of the aspects described herein. The step of contacting the APC with an immune cell or a population of T cells may be performed according to any of the aspects described herein, including any subsequent steps described herein such as incubation or culturing. Activation of an immune cell, such as a T cell, may be measured by any means known to the skilled person. For example, activation may be measured by an increase in the proportion of IFN-γ-positive immune cells, such as T cells. Activation may be measured as the increase in proliferation of the immune cells. In any of the above recited methods, proliferation of the immune cell or the population of T cells specific for an antigen may be increased by at least 10% when compared to an otherwise identical method that does not involve the modulator of SOCE. For example, proliferation may be increased by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100% when compared to an otherwise identical method that does not involve the modulator of SOCE. An increase in proliferation may be calculated by maturing human monocyte-derived dendritic cells for 16 hours with a dendritic cell (DC) maturation cocktail (20 ng / ml TNFα, 15 ng / mL IL-6 and 5 ng / mL IL-1β), followed by addition of an antigen (such as 10µM MLANA16-40(A27L)dissolved in DMSO) for 10 minutes, followed by the addition of the modulator of SOCE (solubilised in DMSO) or a DMSO vehicle, incubation of the DCs for a further 4 hours, washing twice of the DCs in complete medium, and addition of T cells added at a ratio of 2:1 to DCs, incubated at 37˚C, 5% CO2and supernatant collected at 24, 48 and 72 hours. Proliferation of the T cells is then measured. The T cells may be a human antigen-specific effector CD8 T cell clone (grown from a single cell), or a 1:1 mixture of total circulating primary naïve CD4 and CD8 T cells. For methods that do not involve an antigen, an increase in proliferation may be calculated by addition of the modulator of SOCE to PBMCs seeded in a 96-well plates at 2.5 x 106cells / ml, incubating for 4 hours at 37˚C, 5% CO2, transferring cells to a 24 well plate and diluted to 0.5 x 106cells / ml, and incubating for 14 days at 37˚C, 5% CO2, with media changes every 2-3 days. Cells are counted and proliferation is determined by normalisation to cell count at initial seeding. The methods described herein are typically performed in vitro. Modulator of store-operated calcium entry The methods disclosed herein involve contacting an APC with a modulator of store- operated calcium entry (SOCE). The ER is the largest membrane-bound organelle in the cell, and the main intracellular calcium store. SOCE begins via the mobilisation of calcium stored in the ER towards the cytosol, chiefly based on ryanodine (RyR) and / or inositol triphosphate (IP3) receptors present on the ER membranes, but may also be enabled via ER calcium leak channels such as Orai3. Other ER calcium leak channels include Sec61, presenilins, and TRP channels, such as TRPC1, TRPC6, TRPM8, TRPP2 and TRPV1. IP3-receptors (IP3R) are present in all cell types, and are activated primarily by the signaling molecule IP3 as well as cytoplasmic calcium. IP3R may also be activated by FFARs, such as FFAR1 and FFAR4. IP3 is generated downstream of the activation of several different types of receptors that are capable of activating phospholipase C (PL-C) which then hydrolyses phosphatidylinositol 4,5- bisphosphate (PIP2), a phospholipid on the inner leaflet of the PM, generating two important second messengers: IP3 and diacylglycerol (DAG). When persistent or prolonged activation of ER calcium channels leads to ER calcium depletion, the low ER calcium concentration triggers the activation of store-operated calcium entry (SOCE) in order to sustain prolonged signaling as well as to pump calcium back and refill the ER stores to restore its resting state. This activation of extracellular calcium influxes is mediated by calcium release-activated channels (CRAC), a ubiquitous signaling mechanism in both non-excitable and excitable cells. SOCE itself leads to a prolonged increase in the cytosolic calcium levels, and both the elevated cytosolic calcium concentration and the further influx from CRAC channels lead to the activation of different calcium-dependent processes. The main components on the SOCE / CRAC channels are STIM and Orai proteins. Stromal-interaction molecule proteins (STIM1 and STIM2) are ER transmembrane proteins able to sense ER calcium depletion through their luminal EF-hand calcium-binding domain, after which they oligomerize, remodel the ER and translocate proximal to the PM, promoting the formation of ER-PM membrane contact sites (MCS). Within these MCS, STIM1 physically interacts with the PM transmembrane calcium channel Orai (Orai1-3), whose opening allows the influx of calcium into the cytosol. Although STIM / Orai are recognized as the core molecules mediating SOCE, a large number of accessory proteins have also been implicated in SOCE signaling. Notably TRP channels such as TRPC1 / 2 / 4 / 5 / 6 have been shown to bind directly to STIM1 or to operate in conjunction with Orai channels, and all TRPC channels can be activated by DAG. In addition, junctate is an ER transmembrane protein that can interact with TRPC channels, IP3R as well as STIM1, and can mediate signals initiated by store depletion in the absence of STIM proteins. The restoration of ER calcium and STIM calcium-binding, along with feedback inhibition and endocytosis of CRAC channels, then contribute to CRAC channel deactivation and SOCE termination. In parallel to SOCE, there are two main extrusion mechanisms that help return the concentration of cytosolic and ER calcium to their resting levels: the sarco- endoplasmic reticulum calcium-ATPase (SERCA) pumps, which pump calcium ions from the cytoplasm into the ER, refolding STIM1 and ending SOCE, and the PM calcium ATPase (PMCA), which actively transports calcium ions from the cytoplasm to the extracellular milieu. The cytoplasm and ER also contain numerous calcium binding proteins, such as calretinin and calreticulin-calnexin (ER), which bind to the “free” calcium, acting both as buffers as well as effectors that translate calcium signals into changes of cellular function. A modulator of SOCE may therefore be a molecule that modulates the calcium entry resulting from depletion of intracellular calcium stores, namely ER calcium. A modulator of SOCE may therefore be a modulator of PL-C, IP3R, FFAR (e.g. FFAR1 and FFAR4), RyR, a calcium leak channel (e.g. Orai3, Sec61, a presenilin or a TRP channel, such as TRPC1, TRPC6, TRPM8, TRPP2 and TRPV1), CRAC (e.g. STIM and / or Orai proteins), SERCA and / or PMCA. A modulator of SOCE may therefore be a modulator of PL-C, IP3R, RyR, a calcium leak channel (e.g. Orai3, Sec61, a presenilin or a TRP channel, such as TRPC1, TRPC6, TRPM8, TRPP2 and TRPV1), CRAC (e.g. STIM and / or Orai proteins), SERCA and / or PMCA. A modulator of SOCE may therefore be a modulator of PL-C, IP3R, RyR, Orai3, CRAC (e.g. STIM and / or Orai proteins), SERCA and / or PMCA. A modulator of SOCE may be a modulator of IP3R, Orai3, CRAC (e.g. STIM and / or Orai proteins), SERCA and / or PMCA. A modulator of SOCE may be a modulator of SERCA and / or CRAC (such as a modulator of the Orai channel). Typically, the modulator of SOCE is an activator of SOCE. In other words, the modulator of SOCE may be a SOCE stimulator. For example, the modulator of SOCE may activate the depletion of intracellular calcium stores (such as the depletion of ER calcium), activate cytosolic calcium influx (e.g. via IP3R or CRAC channels), and / or inhibit cytosolic calcium efflux (e.g. via SERCA or PMCA). An inhibitor of cytosolic calcium efflux may be an inhibitor of ER calcium refilling (e.g. via SERCA). An activator of the depletion of intracellular calcium stores may also be referred to as an activator of ER calcium release. Accordingly, the modulator of SOCE may be an activator of IP3R, an activator of ER calcium leak channels (such as Orai3), an activator of CRAC, an inhibitor of SERCA or an inhibitor of PMCA. An activator of IP3R may be an activator of FFAR1 and / or FFAR4. The inhibitor of SERCA may be selected from thapsigargin (Tg) or an analogue thereof (e.g. mipsagargin and JQ-FT), 2,5-di(tert-butyl)hydroquinone (DBHQ, TBHQ), artemisinin, CAD204520, Casearin J, Curcumin, CXL017, Gossypol, and sHA 14-1. The inhibitor of SERCA may be selected from thapsigargin (Tg) or an analogue thereof (e.g. mipsagargin and JQ-FT), and 2,5-di(tert- butyl)hydroquinone (DBHQ, TBHQ). The activator of FFAR1 and / or FFAR4 may be In some cases, the modulator of SOCE may be an inducer of ER stress, for example, in combination with one or more of the effects described above. As described herein, many modulators of SOCE have contrasting effects depending on the cell type in which they are used and / or the concentration at which they are used. As demonstrated in the examples, the compound pBr was found to strongly activate SOCE at lower concentrations, but inhibit SOCE at higher concentrations. The exact mechanisms by which pBr achieves these contrasting activities is unknown, but it could be that it acts on opposing molecules involved in SOCE with different binding affinities. Typically, the modulator of SOCE is used under conditions to activate SOCE. The modulator of SOCE is typically used at a concentration to activate SOCE. For example, the modulator of SOCE is used under conditions to activate the depletion of intracellular calcium stores (such as the depletion of ER calcium), activate cytosolic calcium influx (e.g. via IP3R, ER calcium leak channels or CRAC channels), and / or inhibit cytosolic calcium efflux (e.g. via SERCA or PMCA). Suitable conditions may be identified depending on the modulator used through routine experimentation based on the teaching of the application. For example, the methods disclosed herein may involve contacting the APC with an effective concentration of a modulator of SOCE to activate SOCE, e.g. to activate the depletion of intracellular calcium stores (such as the depletion of ER calcium), activate cytosolic calcium influx (e.g. via IP3R or CRAC channels), and / or inhibit cytosolic calcium efflux (e.g. via SERCA or PMCA). The modulator of SOCE may be selected from a SERCA inhibitor (such as thapsigargin (Tg) or an analogue thereof), cyclopiazonic acid (CPA), 2-aminoethyl diphenylborinate (2APB) or a derivative thereof, a C10-C22 fatty acid (e.g. palmitate or oleate), platelet activating factor (PAF), the formylated peptide fMIFIL, DPB162-AE (Mikoshiba compound), and IA65 (4-((5-Phenyl-4-(trifluoromethyl)thiazol-2-yl)amino)benzoic acid). The modulator of SOCE may be selected from thapsigargin (Tg), cyclopiazonic acid (CPA), 2-aminoethyl diphenylborinate (2APB) or a derivative thereof, palmitate, platelet activating factor (PAF), the formylated peptide fMIFIL, DPB162-AE (Mikoshiba compound), and IA65 (4-((5- Phenyl-4-(trifluoromethyl)thiazol-2-yl)amino)benzoic acid). The modulator of SOCE may be selected from thapsigargin (Tg), 2-aminoethyl diphenylborinate (2APB) or a derivative thereof, and palmitate. The modulator of SOCE may be selected from thapsigargin (Tg), and 2-aminoethyl diphenylborinate (2APB) or a derivative thereof. The modulator of SOCE may be 2-aminoethyl diphenylborinate (2APB) or a derivative thereof. The modulator of SOCE may be a derivative of 2-aminoethyl diphenylborinate (2APB). The derivative of 2APB may comprise the formula: , wherein R1is selected from a halogen, preferably, F, Cl, Br or I, more preferably Br, a dimethylsulfamoyl group, and a 2-aminoethoxyphenyl borinyl group, and R2is selected from L-5-hydroxytryptophan (5-OH-Trp), L-methionine (Met) and 2-aminoethanol. For example, R1may be selected from a halogen, preferably, F, Cl, Br or I, more preferably Br, a dimethylsulfamoyl group, and a 2-aminoethoxyphenyl borinyl group, and R2may be 2- aminoethanol. R1may be para-, ortho- or meta-, preferably para-. Where R1is a 2- aminoethoxyphenyl borinyl group, R1is preferably meta-. 2APB, or the derivative of 2APB, may be in an open and / or a closed form. The structures of the open and closed forms are provided in the formula above. The derivative of 2APB may comprise the formula: , wherein R3and R4are independently selected from a halogen, preferably, F, Cl, Br or I, more preferably Br, a dimethylsulfamoyl group, and a 2-aminoethoxyphenyl borinyl group, and R5is selected from l-5-hydroxytryptophan (5-OH-Trp), l-methionine (Met) and 2-aminoethanol. R3and R4may be para-, ortho- or meta-. R3and R4are preferably para- or meta-, more preferably meta-. R3and R4may be the same, i.e. both R3and R4may be a group selected from a halogen, preferably, F, Cl, Br or I, more preferably Br, a dimethylsulfamoyl group, and a 2-aminoethoxyphenyl borinyl group. R3and R4may be independently selected from a halogen, preferably, F, Cl, Br or I, more preferably Br, and a dimethylsulfamoyl group. R3and R4may be independently selected from a halogen, preferably, F, Cl, Br or I, more preferably Br, a dimethylsulfamoyl group, and a 2-aminoethoxyphenyl borinyl group, and R5may be 2-aminoethanol. 2APB, or the derivative of 2APB, may be in an open and / or a closed form. The open and closed forms are provided in the formulae above. The derivative of 2APB may be selected from para-Br-2APB (pBr), ortho-Cl-2APB (oCl), para-F-2APB (pF), ortho-Br-2APB (oBr), ortho-F-2APB (oF), para- dimethylsulfamoyl-2APB (pSO2NMe2), meta-F-2APB (mF), l-5-hydoxytryptophan (5-OH- Trp-2APB), para-I-2APB (pI), bis-meta-Br-2APB, bis-1,3-2APB, or bis-1,4-2APB. The derivative of 2APB may be selected from para-Br-2APB (pBr), ortho-Cl-2APB (oCl), para- F-2APB (pF), 2 ortho-Br-2APB (oBr), ortho-F-2APB (oF), para-dimethylsulfamoyl-2APB (pSO2NMe2), l-5-hydoxytryptophan (5-OH-Trp-2APB) and meta-F-2APB (mF). The derivative of 2APB may be selected from para-Br-2APB (pBr), para-I-2APB (pI), ortho-Cl- 2APB (oCl), para-F-2APB (pF), ortho-Br-2APB (oBr), l-5-hydoxytryptophan (5-OH-Trp- 2APB) and meta-F-2APB (mF). The derivative of 2APB may be selected from para-I-2APB (pI), bis-meta-Br-2APB, para-Br-2APB (pBr), bis-1,3-2APB, or bis-1,4-2APB. The derivative of 2APB may be selected from para-I-2APB (pI), and para-Br-2APB (pBr). The derivative of 2APB may be pBr, e.g. in closed (CAS registration no.85722-09-4) or open form (CAS registration no.85724-96-5). The derivative of 2APB may be pI, e.g. in closed (CAS registration no.1435463-77-6) or open form. The derivative of 2APB may be bis- meta-Br-2APB, e.g. in closed or open form. The derivative of 2APB may be bis-1,3-2APB, e.g. in closed or open form (CAS registration no.1208260-95-0). The derivative of 2APB may be bis-1,4-2APB, e.g. in closed or open form (CAS registration no.29137-42-6). Preferably, the derivative of 2APB is selected from para-I-2APB (pI), bis-meta-Br- 2APB, para-Br-2APB (pBr), bis-1,3-2APB, or bis-1,4-2APB. The derivative of 2APB may be bis-1,3-2APB. The modulator of SOCE may further comprise a palmitoyl (hexadecanoic acid) moiety. For example, the modulator of SOCE may comprise 2-aminohexadecanoic acid-2- aminoethoxydiphenyl borate, or a derivative thereof. The derivative thereof may comprise one or more R groups as discussed above. For example, the modulator of SOCE may comprise 2-aminohexadeaconoic acid-p-Br-2APB, e.g. in open or closed form. Without being limited by theory, it is believed that the palmitoyl moiety boosts cross presentation of exogenous antigen on MHC Class I, through unknown mechanisms. The modulator of SOCE is typically used at a concentration that does not cause toxicity to the APC. Accordingly, the modulator of SOCE may be used at a concentration that maintains at least 80% cell viability when compared to the use of a vehicle (e.g. a control comprising the conditions in which the modulator of SOCE is solubilised, e.g. DMSO). The modulator of SOCE may be used a concentration to increase the cytosolic-free Ca2+ concentration ([Ca2+]c) by at least 10%, such as at least 20%, at least 50% or at least 100% when compared to the use of a vehicle. As described above, the modulator of SOCE is typically used under conditions to activate SOCE. Suitable concentrations of the modulator of SOCE may be determined using routine experimentation by those skilled in the art. For example, Tg may be used at a concentration of at least 0.01 μM, such as at least 0.05 μM or at least 0.1 μM. Tg may be used at a concentration of at most 10 μM, such as at most 5 μM, at most 1 μM, at most 0.5 μM at most 0.2 μM or at most 0.1 μM. Tg may be used at a concentration of 0.01 μM to 5 μM, such as 0.01 μM to 1 μM, 0.01 μM to 0.5 μM, 0.05 μM to 0.5 μM, 0.05 μM to 0.2 μM or 0.05 μM to 0.1 μM. Tg may be used at a concentration of about 0.01 μM, about 0.05 μM, about 0.1 μM or about 0.5 μM, preferably about 0.05 μM or about 0.1 μM. The derivative of 2APB, in particular pI and pBr, may be used at a concentration of at least 0.5 μM, at least 1 μM, at least 2 μM, at least 5 μM or at least 10 μM. The derivative of 2APB, in particular pI and pBr, may be used at a concentration of at most 100 μM, such as at most 50 μM, at most 20 μM or at most 10 μM. The derivative of 2APB, in particular pI and pBr, may be used at a concentration of 0.5 μM to 100 μM, such as 1 μM to 100 μM, 2 μM to 100 μM, 5 μM to 100 μM, 0.5 μM to 50 μM, 1 μM to 50 μM, 2 μM to 50 μM, 5 μM to 50 μM, 0.5 μM to 20 μM, 1 μM to 20 μM, 2 μM to 20 μM, 5 μM to 20 μM, 0.5 μM to 10 μM, 1 μM to 10 μM, 2 μM to 10 μM, or 5 μM to 10 μM. The derivative of 2APB, in particular pI and pBr, may be used at a concentration of about 1 μM, about 2 μM, about 5 μM, about 10 μM or about 20 μM, preferably about 5 μM or about 10 μM. In some cases, the modulator of SOCE is provided on a solid particle. For example, the methods may comprise contacting the APC with an antigen and a solid particle that comprises a modulator of SOCE. The application also provides a solid particle comprising the modulator of SOCE. The solid particle typically has a diameter of at least 0.1 μm, such as at least 0.5 μm, at least 1 μm, at least 2 μm or 3 μm. The solid particle may have a diameter of at most 10 μm, such as at most 5 μm or at most 3 μm. The solid particle may have a diameter of 0.1 μm to 10 μm, such as 0.1 μm to 5 μm, 0.1 μm to 3 μm, 0.5 μm to 10 μm, 0.5 μm to 5 μm, or 0.5 μm to 3 μm. The solid particle may have an average diameter of about 0.1 μm, about 0.5 μm, about 1 μm, about 2 μm, 3 about μm, about 5 μm or about 10 μm. The solid particle may be magnetic. The solid particle may be biodegradable, for example upon contact with a protease, esterase, lipase, glycosidase, acidic and / or oxidative environment (e.g. in a phagosome). The 2APB derivatives, such as pBr and pI, can be linked via the R groups to a solid biodegradable support via cleavable linkers (e.g. ester, disulphide, thiol ene, hydrazine, acetal, ketal linker and the like. The solid particle may be chemically coupled to the modulator of SOCE (e.g. Tg, APB or a derivative thereof) and / or to palmitate. The solid particle may otherwise comprise (e.g. through absorption or adsorption) that modulator of SOCE (e.g. Tg, APB or a derivative thereof) and / or palmitate. Without being limited by theory, it is believed that phagocytosis of particles is itself a stimulus that induces SOCE signals and promotes the capacity of APCs such as DCs to activate immune cells such as T cells, reducing the effective concentration of antigen required for T cell activation. In a further aspect, the invention relates to a compound selected from the group set out below: p-I-2APB (open form): Bis-m-Br-2APB (open and closed forms): Bis-1,4-2APB (closed form): 2-Aminohexadecanoic acid-p-Br-2APB (open and closed forms): To the best of the inventors’ knowledge, these compounds have not been previously generated. These compounds are believed to be novel modulators of SOCE, in accordance with the invention. Without wishing to be bound by theory, it is believed that C10-C22 fatty acids may activate SOCE via the activation of FFAR1 and FFAR4, and / or through other unknown means. The C10-C22 fatty acid may be a saturated (SFA), mono-unsaturated (MUFA), and poly-unsaturated fatty acids (PUFA). The modulator of SOCE may be palmitate or oleate. The modulator of SOCE may be palmitate. The palmitate may be complexed with a carrier molecule. Any suitable carrier molecule may be used. The carrier molecule may be 2APB or a derivative thereof. The carrier molecule may be a molecule known to modulate ER function and / or SOCE. The carrier molecule may be bovine serum albumin (BSA). The carrier molecule may be 2APB or a derivative thereof. Antigen presenting cell The methods of the invention involve contacting an antigen-presenting cell with an antigen and a modulator of SOCE. Any APC is useful with the invention. An APC is a cell that is capable of presenting an antigen on an MHC molecule on the cell surface, e.g. so that it is capable of being recognised by a cell expressing a T cell receptor specific for the antigen. The MHC molecule may be an MHC Class I or an MHC Class II molecule. Preferably, the APC is capable of presenting an antigen derived exogenously (e.g. phagocytosed or endocytosed and partially digested by a protease) on an MHC molecule on the cell surface. The APC may be a naturally occurring cell, or may be synthetic. For example, the APC may be genetically modified (or transiently modified) to express a MHC Class II molecule on the cell surface, or may be modified to enhance expression of cytokines. Typically, the APC is not genetically modified. The APC may be a dendritic cell, a macrophage, B-cell, an epithelial cell, a fibroblast, a thymic epithelial cell, a thyroid epithelial cell, a glial cell, a pancreatic beta cell, a vascular endothelial cell, or a tumour cell. Preferably, the APC is a professional APC. As used herein, a professional APC is a cell that is capable of presenting antigen derived exogenously on an MHC Class II molecule expressed by the cell. Preferably, the professional APC is capable of cross-presentation, e.g. capable of presenting antigen derived exogenously on an MHC Class I molecule expressed by the cell. The professional APC may be a dendritic cell, a macrophage, B-cell, or an epithelial cell. The professional APC may be a bone marrow-derived cell or a peripheral blood mononuclear cell-derived cell. Preferably, the APC is a dendritic cell. The dendritic cell may be a monocyte-derived dendritic cell (MoDC) or a bone-marrow-derived DCs (BMDC). The APC may be a mammalian or non-mammalian APC. Non-mammalian APCs include Zebrafish, Drosophila and Xenopus APCs (all of which are known to express STIM proteins). The APC is preferably a mammalian APC. The mammalian APC may be a human APC. The mammalian APC may be a non-human mammalian APC, such as a rodent cell, a pig cell (e.g. Sus scrofa), a monkey cell (e.g. Macaca mulatta, Macaca fascicularis, or African green monkey i.e. COS cells), marmoset cell (Callithrix jacchus), dog cell, rabbit cell, llama cell or camelid cell. Preferably, the non-human mammalian APC is a rodent cell, such as a mouse cell (e.g. Mus musculus), a rat cell (e.g. Rattus norvegicus) or a Chinese hamster cell (e.g. CHO cells), preferably a mouse cell. For example, the APC may be a professional human APC (e.g. a human dendritic cell) or a professional mouse APC (e.g. a mouse dendritic cell). The invention also relates to an APC (such as a professional APC) obtained or obtainable by the methods disclosed herein. For example, the invention may relate to a professional APC obtained or obtainable by a method comprising contacting the professional APC with a modulator of SOCE and an antigen, as described herein. The APC may be suitable for use as a vaccine, such as a dendritic cell vaccine. Examples of dendritic cell vaccines include Sipuleucel-T and ilixadencel. In the methods disclosed herein, the APC may be present in a population of cells. The population of cells comprising the APC may be PBMCs. Antigen The methods of the invention involve contacting an antigen-presenting cell with an antigen and a modulator of SOCE. Any antigen may be used with the invention. The antigen is typically a molecule that is capable of being exogenously contacted with the APC and subsequently presented by an MHC molecule expressed by the APC. For example, the antigen may be a whole protein, which is phagocytosed, partially digested by a protease, and a resulting peptide presented by an MHC molecule expressed by the APC. The antigen may be tailored to the intended use of the methods or cells described herein. For example, the antigen may be a bacterial, viral, parasitic or tumour antigen. A tumour antigen may be selected from the group consisting of MLANA (Melan-A / MART-1), NY-ESO-1 (New York Esophageal Squamous Cell Carcinoma-1), Carcinoembryonic Antigen (CEA), Alpha-Fetoprotein (AFP), Prostate- Specific Antigen (PSA), PSMA (Prostate-Specific Membrane Antigen). Cancer Antigen 125 (CA-125), Cancer Antigen 15-3 (CA 15-3), Cancer Antigen 19-9 (CA 19-9), Mucin-1 (MUC1), HER2 / neu (ErbB-2), Wilms Tumor Protein (WT1), Melanoma-Associated Antigen (MAGE), BCR-ABL, EGFR (Epidermal Growth Factor Receptor), Mesothelin (MSLN), Glypican-3 (GPC3), Survivin, CD19, CD20, TROP2 (Trophoblast Cell Surface Antigen 2), and VEGFR (Vascular Endothelial Growth Factor Receptor). A viral antigen may be selected from the group consisting of SARS-Cov2 spike protein, Hemagglutinin (HA), Neuraminidase (NA), Hepatitis B Surface Antigen (HBsAg), Human Papillomavirus (HPV) L1 Protein, Dengue Virus Envelope Protein (E Protein), measles Virus Hemagglutinin, Mumps Virus Fusion Protein, Rubella Virus E1 Glycoprotein, Varicella-Zoster Virus (VZV) Glycoprotein E, and Hepatitis A Virus Capsid Protein. A bacterial antigen may be selected from the group consisting of Tetanus Toxin, Diphtheria Toxin, Pertussis Toxin and Filamentous Hemagglutinin, Haemophilus influenzae type b (Hib) Polyribosylribitol Phosphate (PRP), Pneumococcal Surface Protein A (PspA), Meningococcal Factor H Binding Protein (fHbp), Bacillus Calmette-Guérin (BCG) Vaccine Antigens, Outer Membrane Vesicles (OMVs) from Neisseria meningitidis, Cholera Toxin B Subunit, and Anthrax Protective Antigen (PA). A parasite antigen may be selected from the group consisting of Circumsporozoite Protein (CSP), Merozoite Surface Protein 1 (MSP-1), Apical Membrane Antigen 1 (AMA-1), Pfs25 Protein, Glutamate-Rich Protein (GLURP), Leishmania gp63, Toxoplasma gondii SAG1 (Surface Antigen 1), Schistosoma mansoni Tegumental-Allergen-Like (Sm-TAL) Proteins, and Echinococcus granulosus Antigen B (EgAgB). A fungal antigen may be selected from the group consisting of Candida albicans Als3p (Agglutinin-Like Sequence 3 Protein), Candida albicans Sap2 (Secreted Aspartyl Proteinase 2), Candida albicans Hyr1 (Hyphal Wall Protein 1), Aspergillus fumigatus Crf1 (Cell Wall Glycoprotein 1), Aspergillus fumigatus Asp f3, Cryptococcus neoformans GXM (Glucuronoxylomannan), Cryptococcus neoformans CAP59 (Capsular Polysaccharide), Histoplasma capsulatum Hsp60 (Heat Shock Protein 60), Blastomyces dermatitidis BAD1 (Blastomyces Adhesin 1), and Coccidioides spp. T27K (Proline-Rich Antigen). In some cases, the antigen is a tumour lysate (Tlys). The Tlys may be autologous to the subject, i.e. may be obtained from the tumour of a subject to be treated in accordance with the invention. Thus, in some embodiments, the methods described herein comprise contacting an APC with a tumour lysate and a modulator of SOCE. The antigen may be a provided as a combination of different antigens. Immune cell In some aspects, the methods disclosed herein involve contacting an APC obtained according to the methods disclosed herein, or a supernatant derived from the APC, with an immune cell. Without being limited by theory, it is believed that the enhanced antigen presentation achieved by APCs obtained according to the methods disclosed herein result in increased activation of T cells capable of recognising the antigens presented in the context of an MHC molecule. Furthermore, the APCs obtained according to the methods of the invention have also been observed to express a number of co-stimulatory molecules and secrete cytokines and other soluble factors, such as ICAM-1, CXCL11 and CXCL13 among others, which could lead to the activation of a range of immune cells. The immune cell may be a naturally occurring cell, or may be synthetic. For example, the immune cell may be derived from a host, e.g. a patient in need, such as for future use in adoptive cell therapy. The immune cell may be derived from a tumour of a patient, e.g. a patient to be treated. The immune cell may be a tumour-infiltrating lymphocyte. In some cases, the immune cell may be genetically modified (or transiently modified) to express a TCR or a chimeric antigen receptor (CAR) specific for the antigen. The immune cell may be a T cell, a γδ T cell, a CAR-T cell, a natural killer (NK) cell, an NKT cell, an induced pluripotent stem cell (iPSC) derived NK cell (iPSC-NK), a B cell, a phagocyte, an innate lymphoid cell, a mast cell, a monocyte, a dendritic cell (DCs) or a macrophage. Preferably, the immune cell is a T cell. The T cell may be derived from a tumour of a patient. The T cell may be a tumour-infiltrating lymphocyte. T cells express a TCR that are capable of recognising an antigen presented by an MHC molecule and thus may be specifically activated by the APC obtained according to the methods described herein. More preferably, the T cell is a CD8+ T cell, or cytotoxic T cell. Cytotoxic T cells have been demonstrated to particularly benefit from the invention. The T cell may be a CD4-CD8+ T cell. The T cell may be a CD4+ T cell, or helper T cell (TH cell), such as a TH1, TH2, TH3, TH17, TH9, or TFH cells. The T cell may be a regulatory T cell (Treg). The T cell may be a naïve, effector, memory, effector memory, central memory, memory stem T cell. The T cell may be a peripheral lymphocyte. The T cell may be expanded from PBMCs. The T cell may be autologous with respect to a subject into which it is to be administered. The T cell may be allogeneic with respect to a subject into which it is to be administered. The T cell may be partially HLA-mismatched with respect to a subject into which it is to be administered. The T cell may be expanded from a tumour-infiltrating lymphocyte. Accordingly, provided herein a tumour-infiltrating lymphocyte, such as a population of tumour-infiltrating lymphocytes, obtained or obtainable by a method disclosed herein. It has been shown that APCs, such as DCs are capable of activating a range of immune cells through a variety of means. For example, DCs are known to activate NK cells by secreting cytokines such as IFNG, IL-12 and IL-2, and possibly also through direct contacts. Similarly, DCs can activate innate lymphoid cells (ILCs) through cytokine secretion, and some reports also suggest direct DC-ILC contacts via MHC-like molecule: natural cytotoxicity receptors. DCs can activate B cells indirectly through CD4 / Tfh T cell activation, but may also directly activate B cells by retaining and presenting intact antigen. Furthermore, some studies have indicated an interaction between DCs and mast cells that involves the transfer of MHC-II antigen complexes. Sources of immune cells will be known to persons skilled in the art, illustrative examples of which include peripheral blood, peripheral blood mononuclear cells, bone marrow, lymph nodes tissue, cord blood, thymus tissue, tissue from the site of infection, ascites, pleural effusion, spleen tissue, and tumours. The immune cell may be derived from whole blood. An immune cell may be derived from an autologous cell. An immune effector cell may be derived from an allogeneic cell. The term "autologous" refers to any material derived from the same individual to whom the material is later to be re-introduced to the individual. The term "allogeneic" refers to any material derived from a different individual of the same species as the individual to whom the material is introduced. Two or more individuals are said to be allogeneic to one another when the genes at one or more loci are not identical. In some aspects, allogeneic materials from individuals of the same species may be sufficiently genetically distinct to interact antigenically. The immune cell is typically from the same species from which the APC is derived. For example, where the APC is a human cell, the immune cell may be a human immune cell. The immune cell may be a mammalian of non-mammalian immune cell. Non- mammalian immune cell include Zebrafish, Drosophila and Xenopus immune cell. The immune cell is preferably a mammalian immune cell. The mammalian immune cell may be a human immune cell. The mammalian immune cell may be a non-human mammalian immune cell, such as a rodent cell, a pig cell (e.g. Sus scrofa), a monkey cell (e.g. Macaca mulatta, Macaca fascicularis, or African green monkey i.e. COS cells), marmoset cell (Callithrix jacchus), dog cell, rabbit cell, llama cell or camelid cell. Preferably, the non-human mammalian immune cell is a rodent cell, such as a mouse cell (e.g. Mus musculus), a rat cell (e.g. Rattus norvegicus) or a Chinese hamster cell (e.g. CHO cells), preferably a mouse cell. For example, the immune cell may be a human immune cell (e.g. a human CD8+ T cell) or a mouse immune cell (e.g. a mouse CD8+ T cell). The invention also relates to an immune cell (such as a CD8+ T cell) obtained or obtainable by the methods disclosed herein. For example, the invention may relate to a immune cell obtained or obtainable by a method comprising contacting an APC with a modulator of SOCE and an antigen, and contacting the APC with the immune cell. The immune cell may be suitable for use in therapy. For example, the immune cell may be suitable for use as a tumour infiltrating lymphocyte (TIL) therapy, a CAR-T cell therapy or a T cell therapy (e.g. for use in adoptive T cell therapy). An example of a TIL is Lifileucel. Examples of a CAR-T cell therapy are tisagenlecleucel and axicabtagene ciloleucel. Examples of a T cell therapy are BRL03 and afamitresgene autoleucel (Tecelra). Population of T cells In some aspects, the methods disclosed herein involve contacting an APC obtained according to the methods disclosed herein with a population of T cells. Without being limited by theory, it is believed that the enhanced antigen presentation achieved by APCs obtained according to the methods disclosed herein result in increased activation of T cells capable of recognising the antigens presented in the context of an MHC molecule. The population of T cells contacted with the APC is a naïve population of T cells. In this aspect, the method enables T cells specific for the antigen to be activated and expanded, to thereby produce a population of T cells specific for the antigen. The population of T cells may be a population of CD8+ T cells, or cytotoxic T cells. Cytotoxic T cells have been demonstrated to particularly benefit from the invention. The population of T cells may be a population of CD4-CD8+ T cells. The population of T cells may be a population of CD4+ T cells, or helper T cell (TH cell), such as a population of TH1, TH2, TH3, TH17, TH9, or TFH cells. The population of T cells may be a population of regulatory T cells (Tregs). The population of T cells may be a population of effector, memory, effector memory, central memory, or memory stem T cells. The population of T cells may be a population of peripheral lymphocytes. The population of T cells may be a population of CAR-T cells (e.g. CD8+ and / or CD4+). The population of T cells contacted with the APC may be a purified or isolated population of T cells. The methods of activating a population of T cells specific for an antigen may comprise contacting the APC with a population of cells, wherein the population of cells comprises a population of T cells. The population of cells may, for example, be a population of peripheral blood mononuclear cells. The population of T cells may be expanded from PBMCs. The population of T cells may be autologous with respect to a subject into which it is to be administered. The population of T cells may be allogeneic with respect to a subject into which it is to be administered. The population of T cells may be partially HLA-mismatched with respect to a subject into which it is to be administered. Sources of immune cells will be known to persons skilled in the art, illustrative examples of which include peripheral blood, peripheral blood mononuclear cells, bone marrow, lymph nodes tissue, cord blood, thymus tissue, tissue from the site of infection, ascites, pleural effusion, spleen tissue, and tumours. The population of T cells may be derived from whole blood. A population of T cells may be derived from an autologous cell. A population of T cells may be derived from an allogeneic cell. The term "autologous" refers to any material derived from the same individual to whom the material is later to be re-introduced to the individual. The term "allogeneic" refers to any material derived from a different individual of the same species as the individual to whom the material is introduced. Two or more individuals are said to be allogeneic to one another when the genes at one or more loci are not identical. In some aspects, allogeneic materials from individuals of the same species may be sufficiently genetically distinct to interact antigenically. The population of T cells is typically from the same species from which the APC is derived. For example, where the APC is a human cell, the population of T cells may be a population of human T cells. The population of T cells may be a population of mammalian of non-mammalian T cells. Non-mammalian animals include Zebrafish, Drosophila and Xenopus. The population of T cells is preferably a population of mammalian T cells. The population of mammalian T cells may be a population of human T cells. The population of mammalian T cells may be a population of non-human mammalian T cells, such as a population of rodent, a pig (e.g. Sus scrofa), a monkey (e.g. Macaca mulatta, Macaca fascicularis, or African green monkey i.e. COS cells), marmoset (Callithrix jacchus), dog, rabbit, llama or camelid T cells. Preferably, the population of non-human mammalian T cells is a population of rodent T cells, such as a population of mouse (e.g. Mus musculus), rat (e.g. Rattus norvegicus) or Chinese hamster cell (e.g. CHO cells) T cells, preferably a population of mouse T cells. For example, the population of T cells may be a population of human T cells (e.g. human CD8+ T cells) or a population of mouse T cells (e.g. mouse CD8+ T cell). The invention also relates to a population of T cells (such as CD8+ T cells) obtained or obtainable by the methods disclosed herein. For example, the invention may relate to a population of T cells obtained or obtainable by a method comprising contacting an APC with a modulator of SOCE and an antigen, and contacting the APC with a population of T cells. The population of T cells may be suitable for use in therapy. The population of activated T cells specific for an antigen may be further purified according to the methods disclosed herein. The population of activated T cells specific for an antigen may be oligoclonal. The population of activated T cells specific for an antigen may be clonal. Pharmaceutical composition The invention also provides a pharmaceutical composition comprising the APC (such as the professional APC), the immune cell, or the population of T cells specific for an antigen obtained or obtainable by a method disclosed herein. The APC, the immune cell or the population of T cells may be at least 50% of the total cells in the composition, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or at least 99.9% of the total cells in the composition. The total cells in the composition may consist or consist essentially of the APC, the immune cell or the population of T cells, i.e. no other cells are detectable in the composition. The composition may comprise at least about 1x106to about 1x1012of the APCs, the immune cells or the T cells obtained or obtainable according to the methods disclosed herein, such as about 1x106to about 1x1011, about 1x106to about 1x1010, about 1x106to about 1x109, about 1x107to about 1x1011, about 1x108to about 1x1010of the APCs, the immune cells or the T cells obtained or obtainable according to the methods disclosed herein. The composition may comprise about 1x106of the APCs, the immune cells or the T cells obtained or obtainable according to the methods disclosed herein, such as about 5x106, about 1x107, about 5x107, about 1x108, about 5x108, about 1x109, about 5x109, about 1x1010, about 5x1010, about 1x1011, about 5x1011, or about 1x1012of the APCs, the immune cells or the T cells obtained or obtainable according to the methods disclosed herein. The composition may comprise a population of the T cells of the invention in the amounts described above. Typically, the pharmaceutical composition does not comprise the modulator of SOCE and / or the antigen. In other words, the APC, immune cell or population of T cells for use in the pharmaceutical composition have been washed to remove the modulator of SOCE and / or the antigen. The composition may be a pharmaceutical composition. The pharmaceutical composition may comprise a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers comprise aqueous carriers or diluents. Examples of suitable aqueous carriers include water, buffered water and saline. The pharmaceutical composition may include one or more pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects. Examples of such salts include acid addition salts and base addition salts. The composition may comprise one or more additional therapeutic agent, such as a chemotherapeutic agent, an antibiotic agent, an antiviral agent and / or an antifungal agent. The composition may comprise one or more preservative, such as an anti-fungal and / or anti- viral agent. Therapeutic uses Also provided is use of the pharmaceutical composition described herein in a method of treatment of the human or animal body by therapy, or in a diagnostic method. For instance, provided is a pharmaceutical composition according to the invention for use in a method of preventing or treating a disease in a subject. Also provided is a use of a pharmaceutical composition according to the invention for the manufacture of a medicament for the prevention or treatment of a disease in a subject. Also provided is a method of preventing or treating a disease in a subject, the method comprising administering to the subject the pharmaceutical composition of the invention. Also provided is a method of preventing or treating a disease in a subject, the method comprising contacting an APC with an antigen and a modulator of SOCE to thereby produce an antigen-loaded APC, and administering the antigen loaded APC to the subject. Alternatively, a method of treating a disease in a subject may comprise contacting an APC with an antigen and a modulator of SOCE to thereby produce an antigen-loaded APC, contacting the antigen loaded APC with an immune cell or a population of T cells to thereby produce an activated immune cell or a population of activated T cells specific for an antigen, and administering the activated immune cell or the population of activated T cells to the subject. The therapeutic uses and methods may comprise administering a therapeutically effective amount of the APC, immune cell or population of T cells. Also provided is a method of formulating a composition for preventing or treating a disease in a subject, wherein said method comprises mixing an APC, an immune cell or a population of T cells obtained or obtainable according to the method of the invention, with an acceptable carrier to prepare said composition. The disease may be cancer. The disease may be an infection, such as a viral infection, bacterial infection, parasitic infection or fungal infection. The disease may be a prion disease. The disease may be an autoimmune disease. The disease may be an inflammatory disease. The disease may be GvHD. The disease may be a nervous system disease. The disease may be a respiratory disease. The disease may be an allergy. The methods are uses described herein may prevent the disease. For example, the APC may be used as a vaccine, such as a dendritic cell vaccine, to prevent a disease described herein, such as a cancer or an infection. The cancer may be a carcinoma, sarcoma, leukaemia, lymphoma, myeloma or a central nervous system cancer. The cancer may be a solid tumour. The therapeutic methods and uses described herein may comprise inhibiting the disease state (e.g. a cancer), for example by arresting its development and / or causing regression of the disease state until a desired end point is reached. The therapeutic methods and uses of the invention may comprise achieving a partial response, a full response by the cancer. The therapeutic methods and uses of the invention may achieve remission of the cancer. The therapeutic methods and uses described herein may delay the growth of a cancer, arrest the growth of the cancer and / or reverse the growth of the cancer. The therapeutic methods and uses of the invention may reduce the size of the cancer by at least 10%, such as at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or by 100%. Typically, the therapeutic methods and uses are for a human subject in need thereof. However, non-human animals such as non-human mammals are also contemplated. The APC, immune cell or population of T cells is typically from the same species as the subject. For example, where the subject is human, the APC, immune cell or population of T cells may be a human APC, human immune cell or population of human T cells. The subject may be a mammal or a non-mammalian animal. Non-mammalian animals include Zebrafish, Drosophila and Xenopus. The mammal may be a human. The mammal may be a non-human mammal, such as a rodent, pig (e.g. Sus scrofa), monkey (e.g. Macaca mulatta, Macaca fascicularis, or African green monkey i.e. COS cells), marmoset (Callithrix jacchus), dog, rabbit, llama or camelid. Preferably, the non-human mammal is a rodent, such as a mouse (e.g. Mus musculus), rat (e.g. Rattus norvegicus) or Chinese hamster (e.g. CHO cells), preferably a mouse. Typically, the pharmaceutical composition does not comprise the modulator of SOCE and / or the antigen. In other words, the APC, immune cell or population of T cells for use in the pharmaceutical composition have been washed to remove the modulator of SOCE and / or the antigen. Accordingly, the modulator of SOCE per se is not used to treat the disease (e.g. cancer) directly, for example, through cellular toxicity. The dose of the pharmaceutical composition may vary depending on the age and size of a subject, as well as on the disease, conditions and route of administration. The pharmaceutical composition may be administered at a dose of about 1x106to about 1x1012 cells, such as about 1x106to about 1x1011, about 1x106to about 1x1010, about 1x106to about 1x109, about 1x107to about 1x1011, about 1x108to about 1x1010cells. The pharmaceutical composition may be administered at a dose of about 1x106cells, such as about 5x106cells, about 1x107cells, about 5x107cells, about 1x108cells, about 5x108cells, about 1x109cells, about 5x109cells, about 1x1010cells, about 5x1010cells, about 1x1011cells, about 5x1011cells, or about 1x1012cells. The pharmaceutical composition may be administered at a dose of about 1x105cells / kg to about 1x1011cells / kg, such as about 1x105cells / kg to about 1x1010cells / kg, about 1x105cells / kg to about 1x109cells / kg, about 1x105cells / kg to about 1x108cells / kg, about 1x106cells / kg to about 1x1011cells / kg, about 1x106cells / kg to about 1x1010cells / kg, about 1x106cells / kg to about 1x109cells / kg, about 1x107cells / kg to about 1x1011cells / kg, about 1x107cells / kg to about 1x1010cells / kg, or about 1x107cells / kg to about 1x109cells / kg, The pharmaceutical composition may be administered at a dose of about 1x105cells / kg, such as about 5x105cells / kg, 1x106cells / kg, 5x106cells / kg, 1x107cells / kg, 5x107cells / kg, 1x108cells / kg, 5x108cells / kg, 1x109cells / kg, 5x109cells / kg, 1x1010cells / kg, 5x1010cells / kg, or 1x1011cells / kg. The pharmaceutical composition may be administered as a single dose. The pharmaceutical composition may be administered in a multiple dose regimen. For example, the initial dose may be followed by administration of a second or plurality of subsequent doses. The second and subsequent doses may be separated by an appropriate time. For example, the doses may be administered once about every week, once about every 2 weeks, once about every 3 weeks, once about every four weeks, or once about every month. The pharmaceutical composition may be administered intravenously. The pharmaceutical composition may be administered intracranially. The pharmaceutical composition may be administered intraventricularly. The pharmaceutical composition may be administered intradermally. The pharmaceutical composition may be administered subcutaneously. The pharmaceutical composition may be administered intranodally. The pharmaceutical composition may be administered intratumorally. The pharmaceutical composition may be administered intramuscularly. The pharmaceutical composition may be administered intranasally or orally. The pharmaceutical composition may be administered with one or more additional therapy, such as one or more additional therapeutic agents. The additional therapeutic agent may be an anti-tumour agent, an antibiotic agent, an anti-viral agent or an anti-fungal agent. Combined administration of the pharmaceutical composition with the additional therapeutic agent may be achieved in a number of different ways. All the components may be administered together in a single composition. Each component may be administered separately as part of a combined therapy. For example, the pharmaceutical composition may be administered before, after or concurrently with the additional therapeutic agent. The additional therapy may be chemotherapy, radiotherapy and / or surgery. The additional therapy may be an immune checkpoint inhibitor. The immune checkpoint inhibitor may be an inhibitor of PD-1 or PD-L1, such as pembrolizumab, nivolumab, cemiplimab, dostarlimab, atezolizumab, durvalumab oravelumab. The immune checkpoint inihibitor may be an inhibitor of CTLA-4, such as ipilimumab. Prior to administration of a T cell or population of T cells of the invention, the subject may undergo lymphodepletion. Lymphodepletion may be achieved via administration to the subject with fluradabine, cyclophosphamide and / or bendamustine. Lymphodepletion may be carried out for at least about one day, such as about 2 days or about 3 days. The biological activity and / or therapeutic efficacy of the administered pharmaceutical composition may be measured by known methods. For example, the method may comprise imaging, such as magnetic resonance imaging. Uses of the modulator of SOCE The invention also relates to the use a modulator of SOCE for promoting antigen presentation in an APC. For example, the use may be promoting antigen cross-presentation in a professional APC. The further embodiments and aspects discussed above in relation to the methods, APCs, immune cells and populations of T cells, equally apply to the use of the invention. Also provided is the use of a derivative of 2APB as a modulator of SOCE. The derivative of 2APB may be as described herein. For example, the derivative of 2APB may be selected from para-Br-2APB (pBr), ortho-Cl-2APB (oCl), para-F-2APB (pF), ortho-Br- 2APB (oBr), ortho-F-2APB (oF), para-dimethylsulfamoyl-2APB (pSO2NMe2), meta-F-2APB (mF), l-5-hydoxytryptophan (5-OH-Trp-2APB), para-I-2APB (pI), bis-meta-Br-2APB, bis- 1,3-2APB, or bis-1,4-2APB. The derivative of 2APB may be selected from para-Br-2APB (pBr), ortho-Cl-2APB (oCl), para-F-2APB (pF), 2 ortho-Br-2APB (oBr), ortho-F-2APB (oF), para-dimethylsulfamoyl-2APB (pSO2NMe2), l-5-hydoxytryptophan (5-OH-Trp-2APB) and meta-F-2APB (mF). The derivative of 2APB may be selected from para-Br-2APB (pBr), para-I-2APB (pI), ortho-Cl-2APB (oCl), para-F-2APB (pF), ortho-Br-2APB (oBr), l-5- hydoxytryptophan (5-OH-Trp-2APB) and meta-F-2APB (mF). The derivative of 2APB may be selected from para-I-2APB (pI), bis-meta-Br-2APB, para-Br-2APB (pBr), bis-1,3-2APB, or bis-1,4-2APB. The derivative of 2APB may be selected from para-I-2APB (pI), and para- Br-2APB (pBr). The derivative of 2APB may be pBr, e.g. in closed (CAS registration no. 85722-09-4) or open form (CAS registration no.85724-96-5). The derivative of 2APB may be pI, e.g. in closed (CAS registration no.1435463-77-6) or open form. The derivative of 2APB may be bis-meta-Br-2APB, e.g. in closed or open form. The derivative of 2APB may be bis-1,3-2APB, e.g. in closed or open form (CAS registration no.1208260-95-0). The derivative of 2APB may be bis-1,4-2APB, e.g. in closed or open form (CAS registration no. 29137-42-6). The derivative of 2APB may be p-I-2APB (open form), bis-meta-Br-2APB (open and closed forms), bis-1,3-2APB (closed form), bis-1,4-2APB (closed form), or 2- aminohexadecanoic acid-para-Br-2APB (open and closed forms). The modulator of SOCE may further comprise a palmitoyl (hexadecanoic acid) moiety. For example, the modulator of SOCE may comprise 2-aminohexadecanoic acid-2- aminoethoxydiphenyl borate, or a derivative thereof. The derivative thereof may comprise one or more R groups as discussed above. For example, the modulator of SOCE may comprise 2-aminohexadeaconoic acid-p-Br-2APB, e.g. in open or closed form. Definitions It is to be understood that different applications of the methods, uses and SOCE modulators disclosed herein may be tailored to the specific needs in the art. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to be limiting. Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which this invention belongs. In general, the term “comprising” is intended to mean including but not limited to. For example, the phrase “a pharmaceutical composition comprising the professional APC” should be interpreted to mean that the pharmaceutical composition comprises the professional APC, but that the pharmaceutical composition may comprise further components (for example, an excipient). In some aspects of the disclosure, the word “comprising” is replaced with the phrase “consisting of”. The term “consisting of” is intended to be limiting. For example, the phrase “a pharmaceutical composition consisting of the professional APC” should be understood to mean that the pharmaceutical composition contains the professional APC and no further components. In some aspects of the disclosure, the word “comprising” is replaced with the phrase “consisting essentially of”. The term “consisting essentially of” means that specific further components can be present, namely those not materially affecting the essential characteristics of the subject matter. For example, the phrase “a pharmaceutical composition consisting essentially of the professional APC” indicates that the pharmaceutical composition may further comprise one or more excipients that have no particular function. In addition, as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the content clearly dictates otherwise. Thus, for example, reference to “an immune cell” includes two or more “immune cells”. As used herein, the terms “specific for” or "specifically binds" should be understood as meaning that the product with specificity binds to a desired antigen with greater affinity than non-desired antigens. For example, a TCR specific for ovalbumin binds to a peptide derived from ovalbumin, in the context of an MHC Class I or II molecule, with greater affinity than a peptide that is not derived from ovalbumin. Similarly, a T cell specific for ovalbumin should be understood as referring to a TCR that is specific for ovalbumin that is expressed by the T cell. Methods for measuring the affinity of binding are well known in the art. As used herein, the term “about” may be interpreted to mean a value within + / - 10% of the recited value. All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety. The following examples illustrate the invention. Examples Materials and methods Cells All cell culture mediums and supplements were purchased from Gibco unless otherwise specified. Fetal Bovine Serum (FBS, #10270106); penicillin-streptomycin (pen-strep, #P0781, Sigma). All cells were maintained at 37°C, 5% CO2. Cell lines JAWSII cells (#CRL-11904, ATCC) were maintained in alpha-MEM with ribonucleosides, deoxyribonucleosides (#22571), supplemented with 20% FBS, 1% pen / strep, 4 mM L-glutamine (#25030, Gibco), 1 mM sodium pyruvate (#58636) and 5 ng / ml GM-CSF (#315-03, Peprotech). B3Z CD8 T cell hybridoma (a kind gift from Dr. B. Manoury, INSERM, Paris) was maintained in RPMI 25 mM HEPES L-glutamine (#52400025) supplemented with 10% FBS, 1 mM Na / Pyruvate (Na / pyr, #11360039), 1% pen-strep, 50 μm β-mercaptoethanol (#31350010) and 800 μg / mL geneticin (G418, #10131035) to maintain CD8 expression. Mice Wild type (WT) CD45.2 C57BL / 6J and CD45.1 C57BL / 6J were purchased from Charles River Laboratories, France or Italy, or bred in-house at our animal facility at the University of Geneva Faculty of Medicine. OVA257–264-specific TCR transgenic OT-1 CD45.1 mice (derived from C57BL / 6-Tg(TcraTcrb)1100Mjb / J mice, a gift from Prof. S. Becattini, UNIGE) were bred in our animal facility. Genotype was checked by blood sampling and flow cytometry analysis of OT-1 TCR Vβ5.1, 5.2 and CD45.1 expression. All mice (male and female) were bred and maintained under specific-pathogen-free conditions at our animal facility and were used between 8-12 weeks of age. Anesthesia was performed by intraperitoneal injection of 100 μL 13 mg / kg xylazine (Rompun 2%, Bayer) and 65 mg / kg ketamine 10% (Vetoquinol). Euthanasia was performed by intraperitoneal injection of 100 μL 150 mg / kg pentobarbital in 0.9% NaCl (Esconarkon, Streuli Pharma SA). All procedures were approved and performed per the Animal Research Committee of Geneva guidelines under the license numbers GE55 and GE287. Primary murine cells BMDCs were generated by culturing bone marrow cells isolated from mouse femurs and tibias from 6-16-week-old males and females, in DMEM 4.5 g / L glucose L-glutamine (#41965039), supplemented with 10% FBS, 1% pen-strep, 1 mM Na / pyr, 50 μm β- mercaptoethanol and 40 ng / mL GM-CSF, refreshed every 3 days, in non-treated dishes. Non- adherent and semi-adherent cells were harvested and used between days 7 and 10 of culture and verified to be >80% CD11c+MHC-II+ by flow cytometry. Maturation and activation levels were also evaluated by CD80 / 86 and CD40 expression. Naïve CD8+ OT-1 T cells were obtained from OT-1 mouse spleen using the MagniSort Mouse CD8 naïve T cell enrichment kit (#8804-6825-74, ThermoFisher). Cell purity was verified to be >95% CD8a+ by flow cytometry. Primary human cells Human peripheral blood mononuclear cells (PBMCs) were collected from anonymized healthy donors' buffy coats (provided by the University Hospital of Geneva Transfusion Center) by Lymphoprep (#1114545, Axis-Shield) density gradient centrifugation, after HLA- A2 haplotype verification by flow cytometry. Monocytes were isolated using the MagniSort Human CD14 positive selection kit (#8802-6834-74, ThermoFisher) and further differentiated into dendritic cells by culturing in R-10 medium (RPMI GlutaMAX #61870010, 10% FBS, 1% pen-strep) supplemented with 100 ng / mL GM-CSF and 40 ng / mL IL-4 (#300-03 and #200-04, Peprotech), refreshed every 3 days. Non-adherent and semi-adherent cells were harvested and used between days 7 and 10 of culture and their purity was confirmed to be >80% CD11c+HLA-DR+ by flow cytometry. Maturation and activation levels were also evaluated by CD80 / 86 and CD40 expression. Autologous naïve CD4 and CD8 T cells were obtained from healthy donors’ PBMCs by negative selection using the EasySep Human Naïve CD4 or CD8 T cell isolation kit (#17555 and #17968, StemCell), and maintained in R-10 medium supplemented with 100 U / mL rhIL-2 (Proleukin). Antigen-specific CD8+ T cell clones Melan-A / MART-1 specific CD8+ T cell clones were purchased (HD358 #ASTC-1072, HemaCare Cellero, Charles River) or generated in vitro in collaboration with Dr. V. Dutoit. Briefly, Melan-A / MART-1 specific CD8+ T cells were purified from healthy donors’ PBMCs by cell sorting and cloned by limiting dilution culture in the presence of 1 μg / mL Phaseolus Vulgaris Leucoagglutinin (PHA-L, #L-1110-5, Vector Laboratories), feeder cells (allogeneic irradiated PBMCs) and 150 U / mL hrIL-2. Clones were restimulated periodically (every 2-3 weeks). At the end of the expansion, cells were tested again for tetramer positivity (Immatics) by flow cytometry, and response to Melan-A peptide by IFNG production measurement by ELISA, according to manufacturer’s instructions (#88-7316-88, ThermoFisher). Clones were expanded in CTL medium (DMEM 25 mM HEPES, 100 U / mL pen-strep, 8% Human serum (#H4522 Sigma), 1X MEM Non-essential aminoacids (NEAA #11140035), 1 mM Na / pyr) and then maintained in R-10+ medium (RPMI GlutaMAX, 10 mM HEPES (#P05-01100, PanBiotech), 1% pen-strep, 10% FBS (or 8% human serum), 1X MEM NEAA, 1 mM Na / pyr), supplemented with 100 U / mL rhIL-2. Tumor cells and tumor lysate preparation B16-OVA melanoma tumor cells (gift from prof. S. Hugues, UNIGE) were maintained in RPMI with 10% FBS, 1% pen-strep, 50 mM β-mercaptoethanol and 400 μg / mL geneticin (G418) to maintain OVA expression. For tumor lysate (Tlys) preparation, B16-OVA cells were trypsinized, washed with PBS, resuspended to a concentration of 1x107cells / mL, and subjected to 6 consecutive freeze- thaw cycles (FT, 3 min in liquid nitrogen and 3 min at 56°C, respectively). Protein concentration was determined using the Roti-Quant kit (Carl Roth) according to the manufacturer’s instructions, and the number of particles was determined using the Countess II automatic counter (ThermoFisher). Lysates were aliquoted and stored frozen at -80°C, and used at a ratio 1:1 particles with the number of DCs unless otherwise stated. Preparation of phagocytic beads OVA-beads (OVAb) were prepared as follows: 3.0 μm carboxyl polystyrene microspheres (#CP-30-10, Spherotech) were washed 3 times in PBS, activated with 50 mM 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(EDC-HCl) (Carl Roth) in PBS for 15 min at room temperature (RT), followed by 3 washes in borate buffer (0.1 M Na2B4O7). Activated beads were then incubated with 10 mg endotoxin-free chicken ovalbumin (OVA, Invivogen) in borate buffer overnight at 4°C, with shaking. Activation with EDC and covalent coupling with OVA was done a total of 3 times for a three-layer beads preparation. The following day, beads were washed twice with 250 mM glycine in PBS and twice with PBS. Beads were either left unopsonized or further opsonized with anti-OVA (Polysciences). Finally, beads were resuspended in PBS+1%pen-strep, counted using Countess II automatic counter, and used at a ratio 50:1 or 10:1 with the number of DCs according to experimental requirements. In vitro cross-presentation (1) Dendritic cells maturation, antigen-loading and SOCE-drug treatment Murine DCs (JAWSII or BMDCs) were matured overnight with 1 μg / mL LPS (#00- 4976-93, ThermoFisher). Human MoDCs were matured overnight with 5 ng / mL IL-1β (#200- 01B), 15 ng / mL IL-6 (#200-06RC) and 20 ng / mL TNFα (#300-01A) (all from Peprotech). 16h later, DCs were loaded with specific antigens, followed by SOCE-drug treatment 10 minutes after antigen addition. No drug, and / or DMSO (vehicle) at the highest concentration used among the other drugs, were used as controls. Cells were incubated for 4h, after which the supernatant was discarded or collected for cytokine analysis (cytokine array). DCs were washed and used for either downstream analysis or co-cultured with T cells. (2) Co-culture with T cells: Cytokine production and proliferation assays Four hours after antigen-drug addition, DCs were washed twice in complete medium, and T cells were added at a ratio of 2:1 to DCs. Cells were incubated at 37°C, 5% CO2. Supernatant was collected at 24, 48, and 72h for cytokine production evaluation (IL-2 and IFNG ELISA kits, #88-7024-86 (moIL-2), #88-7025-88 (huIL-2), #88-7314-88 (moIFNG), #88-7316-88 (huIFNG), ThermoFisher, according to the manufacturer’s instructions), measured using a Ledetec96 colorimetric plate reader (Labexim Products). T cell proliferation was evaluated by BrdU incorporation using the Cell Proliferation ELISA, BrdU (Chemiluminescent) kit (Roche), incubated for 8h at the specific co-culture times. Substrate was automatically added using a Zephir automatic liquid handler workstation (Perkin Elmer) and luminescence was measured using a SpectraMax L plate reader (Molecular Devices). Cytokine array BMDCs were seeded on 12-mm round #1.5 coverslips in 24-well plates at a density of 2 x 105cells / well and matured for 16h with LPS as above. Cells were either exposed or not (No Bead control) to unopsonized OVAb at 1:10 cell:bead ratio, and 10 min after bead addition were stimulated or not (CTR) with DMSO or SOCE modulators as above and incubated at 37ºC / 5% CO2. After 4h the plates were placed on ice for 5 min and the supernatant collected. A dot-blot Proteome Profiler Mouse Cytokine Array kit, Panel A (#ARY006, R&D Systems), was then performed according to manufacturer’s instructions using 200 μL of BMDC supernatants collected from BMDCs derived from 3 different mice that were pooled and diluted to 1 ml using the kit’s supernatant dilution solution before addition of the capture antibody mix. Array membranes were incubated overnight and detection performed using Immobilon Western Chemiluminescent HRP Substrate (Merck). Images were taken every 10 seconds for 2 min using a LAS-2000 imager (Fujifilm). Densitometry analysis was performed on images after 2 min exposure or 1 min for spots saturated at 2 min using manually define regions of interest using ImageJ v 1.52j software (NIH). Relative luminescence units (RLU) were calculated for each spot by dividing the chemiluminescence intensity signal of each cytokine spot by the mean of the two equivalent cytokine spots on the CTR (OVAb) array. Toxicity measurement - Resazurin reduction assay 25,000 BMDCs per well were seeded in a round bottom non-tissue culture treated 96- well plates. Cells were LPS-matured overnight, loaded with OVAb and treated with the defined drugs for 4 h, after which cells were washed twice in complete medium.20 h later, 15 μg / mL resazurin was added per well, and cells were further incubated for 4 h. At the end of the incubation, the plates were centrifuged and the supernatant was transferred to a black clear-bottom 384w plate to measure fluorescence (Ex560nm-Em600nm) using a Spectramax Paradigm plate reader (Molecular Devices). Relative viability is calculated by dividing well fluorescence values to the average values of untreated cells. Calcium signaling measurements BMDCs were loaded with 4 μM Fluo-8-AM (AAT Bioquest) for 15 min at RT followed by 15 min at 37ºC and last 15 min at RT, in modified Ringer’s solution (140 mM NaCl, 5 mM KCl, 1 mM MgCl2, 20 mM HEPES, 1 mM CaCl2, 10 mM Glucose) containing 500 μM sulfilpyrazone and 0.04% pluronic. At the end of the incubation, cells were resuspended in modified Ringer’s solution with 500 μM sulfinpyrazone (CA) and 10,000 cells per well were seeded in a black optical clear-bottom 384w plate. Calcium signaling was measured using either a one-step or a two-step protocol. In the one-step protocol cells were preincubated for 5 min in control CA base medium, or CA base medium containing GSK-7975A (10 µM) or Xestospongin C (10 µM) prior to addition of SOCE-modulator at the indicated concentration. In the two-step protocol, cells were exposed (or not) to a calcium-free media (CF) by the addition of 2 mM EGTA. After 5 min incubation, SOCE-drugs were added, and fluorescence (490 / 525nm) was measured to evaluate the emptying of ER stores. This signal was recorded for 10 min. Subsequently, SOCE activity was measured by the re-addition of extracellular calcium (4 mM CaCl2) to evaluate calcium influx (SOCE). All measurements were done using FDSS microCELL (Hamamatsu) with built-in robotic pipettor for addition of EGTA, drug and CaCl2 solutions. Analysis of fluorescence values was performed using MS Excel. Normalized fluorescence values are expressed as F / F0 ratio where F0 is defined as the average well fluorescence value during 1 min prior to solution change. Area under the curve and maximum (peak) F / F0 values were calculated using Prism v10.0 (GraphPad). In vitro migration 1.2 to 2x105LPS-matured, SOCE-treated BMDCs were resuspended in 400 μL phenol- free serum-free complete medium (migration medium) and transferred to the upper layer of a 8 μm pore polycarbonate membrane insert (Corning). Transwell inserts were placed onto a 24-well plate containing 400 μL migration medium supplemented with 100 ng / mL CCL21. Cells were incubated overnight at 37°C 5% CO2. The following day, migrated cells were recovered from the bottom wells, labeled with 2.5 μM DRAQ5 and counted by flow cytometry. Numbers are normalized by the average of total cells per day. Bulk RNAseq 1x106MoDCs from 3 different healthy donors were matured overnight with the cytokine cocktail, loaded with Melan-A antigen and treated with SOCE-drugs or no drug as a control, for 6h at 37°C 5% CO2. After incubation, cells were collected, washed once and resuspended in RNA lysis buffer. Total RNA was extracted using the Monarch Total RNA miniprep kit (#T2010G, New England Biolabs), according to manufacturer’s instructions. RNA quantification was performed with a Qubit fluorimeter (ThermoFisher) and RNA integrity was assessed with a Bioanalyzer (Agilent Technologies). The Illumina Stranded mRNA Prep kit (Illumina) was used for the library preparation with 200 ng of total RNA as input. Library molarity and quality were assessed with the Qubit and Tapestation (Agilent Technologies). Libraries were sequenced on a NovaSeq 6000 sequencer (Illumina) using 100‐ bp single‐end reads protocol at the iGE3 Genomics Platform of the University of Geneva (https: / / ige3.genomics.unige.ch / ). Quality control was performed with FastQC v.0.11.9. The reads were aligned to the human Ensembl genome GRCh38. The gene expression was quantified. Filtering out lowly expressed genes, normalization and differential expression analysis were performed. Statistical significance was assessed with a general linear model, negative binomial distribution, and quasi-likelihood F test. Genes with a fold change > 2 and p-value < 0.05 (with multiple testing Benjamini and Hochberg False Discovery Rate correction) were considered differentially expressed. Over-representation analysis of Gene Ontology terms and KEGG pathways were performed with the R / Bioconductor packages: clusterProfiler v.4.9.0 and org.Hs.eg.db 3.15.0. In vivo migration BMDCs from CD45.1 mice were LPS-matured, loaded with OT-I-L (or no antigen as a control, CTR), SOCE-drug-treated (or DMSO as a control) and stained with 5 μM CFSE (ThermoFisher) for 10 min at 37°C. Cells were washed twice, and mixed at 1:1 ratio with LPS-matured, OT-I-L-loaded (or CTR) untreated cells and 1x106total cells in 20 μL PBS were injected subcutaneously in the footpads of CD45.2 recipient mice, previously anesthetized.24h later, mice were euthanized and popliteal lymph nodes (pLN) were harvested. Cell migration was evaluated by flow cytometry using CFSE (for treated), CD45.1 and CD11c antibodies. In vivo cross-presentation Naïve CD8+ OT-1 T cells were labeled with 5 μm CFSE (ThermoFisher) for 10 min at RT and washed 3 times. Cells were adjusted to a concentration of 2x107cells / mL in PBS, and 100 μL CFSE-labeled cells were intravenously injected (tail-vein) into CD45.2 recipient mice. One day later, mice were anesthetized and subcutaneously injected in the footpad with 1x106of LPS-treated, antigen-loaded / unloaded, drug-treated CD45.1 BMDCs, in 20 μL PBS.48h later, “draining” (dLN) and contralateral (CtrlLN) popliteal lymph nodes were harvested, and CFSE dilution and number of CD45.1+ CD8+ OT-1 cells were analyzed by flow cytometry, as well as their activation by CD25 and CD69 surface markers expression. In vivo tumor progression and vaccination WT CD45.2 C57BL / 6J recipient mice were anesthetized and inoculated with 2.5x105B10-OVA tumor cells in 100 μL PBS, by subcutaneous injection into their right flank. Tumor surface was monitored blindly every 1 to 2 days using a caliper and calculated using the formula length × width. When the tumor reached an average surface of 20-25 mm2, mice were anesthetized and received the first dose of DC-vaccine (1x106cells / 20μL PBS of LPS- matured, antigen-loaded, SOCE drug-treated CD45.1 BMDCs), or PBS as a control, via subcutaneous injection into the footpad.6-7 days later, mice were anesthetized and received the second dose of the DC-vaccine. Mice having a tumor size bigger than 15 mm diameter, or showing signs of tumor necrosis and / or suffering were euthanized according to exclusion criteria. Tissue processing and preparation for flow cytometry For in vivo migration and in vivo cross-presentation experiments, popliteal lymph nodes (pLN) were smashed and filtered through a 70 μm mesh filter, washed twice in FACS buffer (PBS 0.5% BSA 5 mM EDTA) and subsequently stained with antibodies. For in vivo tumor experiments, tumors, pLN and tumor-draining inguinal lymph nodes (iLN) were cut into small pieces with scissors, and digested in 1 mg / mL collagenase D (Roche) and 10 μg / mL DNase I (Roche) in HBSS for 40 min at 37°C, mixing up and down every 10 min. The digested cell solutions were filtered through a 70 μm strainer and washed once in FACS buffer. Tumor samples were transferred to a new tube containing lympholyte cell separation media (#CL5035, Cedarlane), centrifuged, and the interphase containing living cells was collected and washed once in FACS buffer. All cells were counted and 2x106cells per sample were analyzed by flow cytometry. Flow cytometry (FC) Single-cell suspensions were incubated with Fc Block (anti-CD16 / 32 FcgRII-RIII) for 15 min at 4ºC and then stained with antibodies in PBS or FACS buffer for 20-30 min at 4ºC, light-protected. Intracellular staining was performed using the intracellular Fixation and Permeabilization Buffer Set (Fix / Perm Concentrate (#00-5123-43, Invitrogen), Fix / Perm Diluent (#00-5223-56, Invitrogen), Permeabilization buffer (#00-8333-56, Invitrogen)) and stained for 45 min at RT, light-protected. For intracellular cytokine staining, cells were first restimulated in complete RPMI containing 100 ng / mL PMA (#P1585-1MG, Sigma-Aldrich), 1 μg / mL ionomycin (#I0634-1MG, Sigma-Aldrich) and GolgiStop solution (1 / 1000, #51- 2301KZ, BD Biosciences) for 4h at 37°C, 5% CO2. To extrapolate total cell numbers, counting beads (ThermoFisher) were added right before running the samples. Data were acquired with a Fortessa analyzer (BD) or Cytoflex S (Beckman) and analyzed using FlowJo software. Immunofluorescence (IF) OVA (Ag) degradation assay BMDCs were seeded on 12-mm round #1.5 coverslips in 24-well plates at a density of 2 x 105 cells / well and matured for 16 h with LPS as above. Cells were either exposed or not to OVAb at 1:10 cell:bead ratio and exposed or not (CTR) to DMSO, or SOCE modulators as above 10 min after bead addition. After 4 h half of the plate was placed on ice for 5 min and supernatant was removed and replaced with 1:1 volume of 4% PFA / PBS solution for 10 min. Cells were then washed with 0.1% NaBH4 / PBS solution for 1 min, washed 2x in PBS, permeabilized in 0.1% Triton-X100 / PBS for 5min and washed 3x PBS. Coverslips were transferred to a humid chamber and blocked in ImageIT-FX (ThermoFisher) for 30 min, in 2% BSA / PBS for 30 min and incubated overnight at 4oC in primary anti-OVA antibody diluted in 0.2% BSA / PBS. Coverslips were washed 3x in PBS and incubated in secondary goat-anti-rabbit AF488 antibody for 1h at room temperature. Cells were washed 3x in PBS and incubated with 1 μg / ml Hoechst 33342 (ThermoFisher) / PBS for 5 min prior to the final wash. Coverslips were mounted in Prolong Diamond (ThermoFisher) anti-fade and sealed with nail-polish. Imaging of brightfield, Hoechst (Ex405:Em460 / 50nm), and AF488 (Ex488:Em525 / 50nm) was performed using a Nipkow Okagawa Nikon spinning disk confocal imaging system equipped with a Plan Apo 63x / 1.4 Oil DICIII objective and Visiview software (Visitron Systems). Image analysis and mean cellular OVA (AF488) fluorescence was quantified by manually defining total cell regions of interest at a single mid- nuclear plane using the brightfield and Hoechst channels. Statistical Analysis All experiments were done with at least 2 independent biological replicates, each with at least 2-3 technical replicates, unless otherwise stated in the figure legends. Statistical analyses were performed defining n as the number of biological samples. GraphPad Prism v10 (GraphPad Software Inc., USA) was used for statistical data analysis. Unpaired two-tailed T test for comparison between two groups, one-way or two-way ANOVA followed by post-hoc Tukey’s or Dunnett’s multiple comparison test were employed to determine the statistical difference between multiple groups. Example 1 - SOCE activators boost murine DCs cross-presentation Whether treatment with SOCE activators might enhance the cross-presentation efficiency of DCs was investigated. As a proof of principle, the commercially available and widely used SOCE-activator SERCA inhibitor thapsigargin (Tg) was first tested in primary murine BMDCs for its capacity to potentiate T cell responses to antigen-loaded DCs. BMDCs were matured by TLR4 engagement with LPS for 16 h prior to antigen loading with OVA - coated beads (OVAb) for 4 h. LPS was chosen as an already potent bench-mark maturation stimulus that would allow comparison with numerous studies. The cells were then washed and irradiated to prevent further BMDC proliferation, prior to co-culture with OVA-specific OT-1 CD8+ T cells for 72h. Indeed, BMDCs treated with Tg displayed significantly increased CD8+ T cell proliferation compared with untreated controls, as measured by uptake of bromodeoxyuridine (BrdU) (Fig.1A). Whether this boosting effect was a generalized phenomenon that did not depend on irradiation was then evaluated by testing combinations of unirradiated primary cells (BMDC and OT-1 CD8+ T cells), the JAWSII BMDC-like cells line, the B3Z OVA-responsive CD8 T cell line, as well as different antigen formats. OVAb was used as above, as well as a lysate of B16 melanoma tumor cells expressing OVA (Tlys) that includes particulate (phagocytosable) cell debris as well as soluble proteins, and has been employed in DC-vaccine designs due to its broad range of tumor-associated antigens. In addition, the soluble peptide OT-I-L (KMFVESIINFEKL), a long version of the minimal OVA257-264peptide epitope, OT-I, that requires processing to be presented, was employed since it is a convenient surrogate antigen for DC-vaccines when tumor lysates are unavailable that elicits superior T cell responses in vivo as compared to minimal peptide or full-length proteins (Fig.1B). Thus, JAWSII DCs and BMDCs were loaded with either OVAb, OT-I-L or Tlys in the presence of Tg or DMSO vehicle control, and co-cultured with B3Z or OT-1 CD8 T cells. After 24h, IL-2 was measured by ELISA as an indication of T cell activation and successful cross-presentation. The enhancing effect of Tg was recapitulated in all the combinations, including the JAWSII / B3Z co-cultures, indicating that these cells lines would be sensitive surrogates useful for screening further potential activators. Thus, next, the effect of 13 SOCE modulators, including Tg and recently characterized derivatives of the known SOCE modulator 2-aminoethyldiphenylborinate (2APB) (Schild et al (2020) International Journal of Molecular Sciences. Multidisciplinary Digital Publishing Institute (MDPI)) were screened for their ability to boost DCs cross-presentation, where the concentrations were chosen based on published ranges for activating SOCE (Fig.1C). Tg and p-Br-2APB (hereafter pBr) (Fig.1D), showed the highest potential and were chosen for further characterization using primary murine BMDCs in co-culture with naïve OT-1 CD8 T cells. Using the strongest antigen format, OVAb, a concentration curve of the drugs was performed and the cross-presentation responses were compared to no drug (CTR) and DMSO vehicle controls. Levels of IL-2 cytokine production were measured as an indication of overall T cell activation and potential expansion, and IFNG production, as an indication of activation and polarization towards effector phenotype. The IL-2 response showed a hormetic dose-response curve where low doses were stimulatory, while higher doses became inhibitory (Fig.1E). In contrast, the high-dose inhibition was less evident in the IFNG response curve (Fig.1F), although both responses peaked in the same range of concentrations. Next, using these optimized concentrations, a more extensive analysis of the drugs’ effects on primary cells was conducted with different antigen formats. Overall, both drugs improved the OT-1 T cell responses to BMDCs loaded with soluble (OT-I-L), particulate (OVAb), or B16-OVA tumor lysate (Tlys) antigen formats (Fig.1G-H). Notably, however, some differences in the effects of these drugs across the different antigens were observed. Tg consistently demonstrated significant boosts in overall T cell activation, as measured by IL-2 production, with all antigen formats (Fig.1G). Additionally, Tg exhibited a smaller but significant effect on IFNG production when BMDCs were loaded with Tlys, but only a small trend with OVAb and no apparent effect with OT-I-L (Fig.1H). In contrast, pBr treatment showed significant increases in IL-2 production with both OT-I-L and OVAb antigens but not with Tlys, while it was able to induce a significant increase in IFNG production with the 3 antigens, especially pronounced with OT-I-L and OVAb. Furthermore, the drugs were tested at the two best concentrations for their ability to promote proliferation using non-irradiated BMDCs. Though in this case all antigen-dependent signals were in general low compared to unloaded BMDCs, pBr induced a slight enhancement in T cell proliferation when BMDCs were loaded with OT- I-L and OVAb, but not with Tlys, whereas Tg only significantly boosted T cell proliferation in the Tlys condition (Fig.1I). Of note, at the higher concentration, Tg also induced a small non-specific proliferation in the no-antigen control (CTR) condition, potentially masking effects in the OT-I-L and OVAb conditions. These results demonstrate that some (though not all) SOCE modulators, namely Tg and pBr, can enhance DCs cross-presentation efficiency across various antigen formats, with distinct effects on T cell activation and proliferation. In auxiliary experiments, additional SOCE modulating compounds and concentrations were tested. First, the effect of palmitate (complexed with carrier molecule bovine serum albumin (BSA)), a lipid previously linked to modulating ER function as well as SOCE, was tested for its ability to improve cross-presentation using combinations of either OVAb-loaded JAWS, or OVAb or Tlys-loaded BMDCs with B3Z as above. Palmitate treatment of 250 µM- 1mM showed significant increases in IL-2 production (Fig.2A-B). Next, a compound of similar structure to pBr, 2APB-pI (pI), but with slightly higher ER-calcium releasing activity than pBr in breast cancer cells, was tested using OVAb-loaded BMDCs in co-culture with OT-1 cells. The IL-2, and to a lesser extent the IFNG responses showed hormetic dose- response curves, similar to pBr (Fig.2C-D). Finally, in a secondary screen using OVAb- loaded JAWS and B3Z co-cultures, 2APB itself, as well as several 2APB analogs, the reversible SERCA inhibitor cyclopiazonic acid (CPA), Tg and natural SOCE modulator platelet activating factor (PAF) were tested at different concentrations. Several compounds showed concentration-dependent potential for improving IL-2 responses, further indicating that the concentration at which a SOCE modulator is applied is a key parameter for producing improved T cell responses. Example 2 - SOCE modulators enhance in vivo BMDCs cross-presentation Given the promising results observed in murine in vitro cross-presentation assays, we aimed to explore the therapeutic implications of SOCE modulators in augmenting DC-based vaccination in vivo. However, before translating these findings to an in vivo setting, it was essential to assess their impact on DC viability and migration, crucial factors for the efficacy of DC-vaccines. High concentrations of Tg have been described to induce ER stress-mediated cell death, while previous studies on pBr showed no toxicity. Moreover, STIM1 ablation has been previously found to reduce DCs migration, hence we wondered whether SOCE modulators could conversely boost it. The potential cytotoxic effects of the SOCE modulators Tg and pBr on BMDCs were thus examined over a 24h period, using the resazurin reduction assay. At the concentrations optimal for boosting cross-presentation, SOCE modulators did not induce significant toxicity in BMDCs compared to untreated cells, both in unloaded cells (CTR) as well as in OVAb-pulsed BMDCs (OVAb) (Fig.3A). Furthermore, in vitro migration assays using trans-well chambers revealed that SOCE modulators did not impair the BMDCs’ ability to directionally migrate towards a CCL21 gradient, a key chemokine for lymph node homing, where no significant migration was observed in the absence of CCL21 as expected (Fig.3B). Interestingly, in a pilot experiment, BMDCs loaded with OVAb exhibited a notable diminished migration, indicating a disadvantage to the use of this antigen format in vivo. In addition, despite extensive washing, un-ingested OVAb could not be reliably separated from the BMDCs after phagocytosis, which represented a potential confounding variable for assessing the effects of drug treatment in the context of an in vivo injection. Consequently, and despite being the condition giving the highest signal in in vitro cross-presentation assays, this antigen format was excluded in subsequent in vivo experiments. Thus, whether SOCE modulators could alter BMDC migration in vivo was investigated next. To this end, subcutaneous injection of BMDCs isolated from CD45.1 mice and treated or not with OT-I-L and SOCE modulators or DMSO controls into the footpad of CD45.2 recipient mice revealed a non-significant trend for reduced migration to the draining popliteal lymph node with Tg in the absence of antigen (Fig.3C). Nevertheless, BMDCs loaded with soluble OT-I-L, despite lower than the CTR, exhibited comparable migration levels between SOCE-treated and DMSO-vehicle controls. These findings indicate that SOCE modulators do not significantly diminish the viability or migration capacity of DCs, supporting their utility on the preparation of DC-based vaccines. To assess the impact of SOCE-activated BMDCs on in vivo cross-presentation, we injected carboxyfluorescein-succinimidyl ester (CFSE)-labeled CD45.1 OT-1 CD8+ T cells intravenously, followed by subcutaneous injection of OT-I-L-loaded or control-unloaded BMDCs into the footpad of the same CD45.2 recipient mice 24h after. Two days post- injection, popliteal lymph nodes from the injected leg (draining, dLN) and the contralateral ones (CtrlLN) were harvested, and evaluated the proliferation of the OT-1 cells, detected as a dilution of the CFSE fluorescence together with increased numbers of total cells, as a measure of cross-presentation. Both drugs were able to improve the DC-vaccine’s ability to induce OT-1 CD8 T cell proliferation (Fig.4A-B). In all conditions, OT-1 cells were essentially absent in the CtrlLN, indicating that the observed increase in OT-1 CD8 T cells number was induced by the DC-vaccine (DCVAC). Notably, a significant antigen-specific increase in the total number of OT-1 T cells dLN was only observed for pBr, though a trend could be discerned for the DMSO and Tg conditions (Fig.4A). Furthermore, the CFSE dilution of the OT-1 cells was also significantly reduced in the groups vaccinated with antigen-loaded Tg- treated BMDCs and pBr-treated BMDCs compared to DMSO-treated, corroborating enhanced proliferation in these conditions (Fig.4B). On the other hand, assessment of CD25+CD69+ staining indicated increased activation levels of OT-1 cells in the DC-vaccine with unloaded Tg-treated BMDCs, while no differences were observed in the DC-vaccine conditions with OT-I-L loaded BMDCs (Fig.4C), suggesting that in the absence of target cells, OT-1 CD8 T cells are not overstimulated by SOCE modulator treatment. CFSE and activation markers were only analyzed in the dLN, due to the low number of OT-1 cells present in the CtrlLN. Despite the low levels of antigen-specific T cell activation elicited in these experiments, due in part to an unexpectedly high level of non-specific activation, observed both in vitro and in vivo, these findings nevertheless emphasize the potential of SOCE modulators in enhancing the effectiveness of DC-based vaccination approaches by promoting CD8+ T cell proliferation in vivo. Example 3 - Mechanistic insights into the enhancing effect of SOCE-modulating drugs on murine DC-mediated T cell responses In our pursuit to elucidate the mechanisms underlying the action of SOCE-modulating drugs, the intracellular calcium signaling induced by Tg and pBr treatment (Fig 5A-C), as well as the contribution of ER calcium release versus plasma membrane influx activity (Fig. 5D-E), were assessed with the fluorescent calcium indicator Fluo-8. To assess the involvement of the primary SOCE molecules Orai or IP3R channels in the calcium signals induced by the drugs, cells were treated with the Orai inhibitor GSK-7975A (GSK) or the IP3R antagonist Xestospongin C (Xesto), prior to SOCE-drug treatment. In calcium- containing medium the two drugs at their optimal concentrations produced a small but significant increase in net cytosolic calcium (ΔPeak) as compared to control (CTR addition of similar volume of medium without drug or vehicle) that was similar across the two SOCE modulators (Fig.5A). Pre-treatment with either GSK (Fig.5B) or Xesto (Fig.5C) decreased these signals to levels similar to CTR and DMSO conditions, confirming the involvement of SOCE components in the drug-induced signals. Then, to assess the ER calcium release component of the signal, Fluo-8-loaded cells were first treated with the SOCE-drugs in calcium-free modified Ringer’s solution. Area under the curve (AUC) measurement showed that although pBr at 5 µM had slightly lower induction of intracellular calcium signaling compared to Tg, pBr 10 µM has comparable levels to Tg’s (both 0.1 µM and 0.05 µM) induced release from ER stores (Fig.5D). Next, extracellular calcium was re-added to the medium in order to evaluate calcium influx (SOCE). In this case, SOCE was more strongly induced by Tg as compared to pBr, at both concentrations (Fig.5E). Since SOCE and calcium signaling, at least alone, might not completely explain the differences in their effect on cross-presentation, we also examined their impact on the three essential signals provided by BMDCs during T cell activation, since the three might be affected by calcium signaling. Signal 1, mediated by the peptide-MHC-I complex (MHC-I-p), was initially hypothesized to drive the observed boosting effect. However, flow cytometry analysis of BMDCs loaded with various antigens and treated with SOCE modulators for 4h revealed unchanged surface levels of MHC-I-p in all the antigen formats tested (Fig.6A), with a surprising absence in cells exposed to particulate antigens (OVAb), despite their high efficacy in vitro. Ongoing investigations are focused on determining whether these complexes are retained intracellularly or maybe secreted. Interestingly, quantification of antigen levels by immunofluorescence revealed significant differences in antigen processing in cells exposed to Tg but not pBr (Fig.6B), which might indicate that Tg acts in pathways of antigen processing favoring cross-presentation, or that intact antigen might be retained for longer periods of time allowing its later transfer to other immune cells. Subsequent examination of signal 2, assessed through CD86 (Fig.6C) and MHC-II (Fig.6D) surface expression, as key indicators of DC activation and maturation, respectively, also did not show significant differences post-drug treatment. For the signal 3, ELISA measurement of IL-12 secretion, a pivotal cytokine in DC- induced T cell activation, also showed no significant differences (Fig.6E). However, dot- blot-based cytokine array containing a panel of 40 different cytokines and chemokines (Fig. 6F) (full dataset not shown) revealed potential upregulation of CXCL13, CXCL11, and soluble ICAM-1 secretion in supernatants of BMDCs loaded with OVAb and treated with either Tg or pBr, factors involved in T cell chemotaxis and T cell activation, suggesting a novel pathway through which SOCE-activated BMDCs may modulate T cell responses. Example 4 - SOCE modulators boost cross-presentation in human DCs Next, whether these effects could be translated to human cells was assessed. To this end, monocyte-derived dendritic cells (MoDCs) were generated from PBMCs isolated from buffy coats from HLA-A2+ healthy donors. MoDCs were matured overnight with IL-1β, TNFα and IL-6, then pulsed with Melan-A16-40(A27L)peptide (hereafter MLANA-L; GHGHSYTTAEELAGIGILTVILGVL), a longer version of the minimal peptide Melan-A26-35(A27L), that includes sequences compatible with both Class I and Class II HLA molecules (HLA-A201 and several HLA-DR and HLA-DQ isoforms), or no antigen (CTR). Cells were then treated with our SOCE drugs at the two best concentrations that were determined using murine cells, and co-cultured with an allogeneic Melan-A-specific CD8 effector T cell clones, or with allogeneic HLA-A2+ naïve CD4 and CD8 T cells (autologous to each other), though HLA-DR or -DQ typing was not performed. IL-2 and IFNG cytokine production were measured by ELISA from supernatants collected at 24, 48 and 72h co-culture, and proliferation was measured by BrdU incorporation at 72h co-culture (Fig.7). When MoDCs were co-cultured with Melan-A-specific effector CD8+ T cell clones (Fig.7A-D), the treatment with 0.1 μM Tg significantly increased IL-2 and IFNG production at all time points measured (Fig.7A-B), albeit with a large antigen-independent effect observed at 72 h, that could be in part due to uncharacterized HLA mismatches (Fig.7B). Conversely, 10 μM pBr treatment did not show any significant effect on IL-2 but significantly increased IFNG production at 24 and 48h (Fig.7B). Regarding proliferation, both Tg (0.05 μM) and pBr (10 μM) induced a small increase in proliferation of the clones, specifically in the Melan-A pulsed conditions, at 72 h, compared with the no drug controls (CTR) (Fig.7C). In a pilot auxiliary experiment, treatment of MoDCs with the pI analog at 5 μM induced a significant increase in the IFNG response at 72h (Fig.7D). When co-culturing MoDCs with naïve T cells (Fig.7E- H), Tg treatment at both concentrations consistently significantly boosted IL-2 and IFNG production at all timepoints (Fig.7E-G) where an antigen-independent activation was also observed at 72h with the higher concentration (Fig.7F). Similarly, pBr treatment led to a significant increase in IL-2 production by the naïve T cells at 24 and 48 h (Fig.7E). However, unlike with murine cells, pBr-treated MoDCs did not significantly increase IFNG production by naïve T cells, at any concentration and times tested (Fig.7E). Finally, in terms of proliferation, Tg 0.05 μM and pBr at 10 μM significantly increased the proliferation of naïve T cells, although irrespective of the presence of the MLANA-L antigen, where, as above, the presence of unknown allogeneic antigens may induce apparently antigen-independent effects that mask specific effects (Fig.7G). On the other hand, in a pilot auxiliary experiment, treatment with 5 μM pI produced a trend towards increased IFNG at 72h that warrants further investigation (Fig.7G). These findings indicate that the effects of SOCE modulators are translatable to human MoDCs and may be even more potent in human cells than in mice at improving DC cross-presentation, highlighting their therapeutic potential for improving DC- and / or T cell-based therapies. Example 5 - Mechanistic insights into the enhancing effect of SOCE-modulating drugs on human DC-mediated T cell responses In order to evaluate the impact of SOCE activation in human cells we performed analysis of transcriptional profiles by bulk RNAseq analysis. A preliminary analysis indicated the presence of only 7 significantly differentially expressed genes between pBr- treated MoDCs and their paired untreated controls (MT2A, metallothionein 2A – ENSG00000125148; MT1G, metallothionein 1G – ENSG00000125144; MT1X, metallothionein 1X – ENSG00000187193; MT1F, metallothionein 1F – ENSG00000198417; MT1E, metallothionein 1E – ENSG00000169715; OLMALINC, oligodendrocyte maturation- associated long intergenic non-coding RNA – ENSG00000235823; ABCA1, ATP binding cassette subfamily A member 1 – ENSG00000165029). Tg treatment induced the significative differential expression of 1915 genes, both upregulated and down-regulated compared to their paired untreated controls. Moreover, a preliminary pathway enrichment analysis of the differentially expressed genes after Tg treatment showed the enrichment of pathways involved in relevant processes such as T cell activation, migration, chemokine production, ER stress or calcium transport. Table 1. Example 6 - SOCE modulators enhance the efficacy of an anti-melanoma DC-vaccine Next, given the promising results observed with both murine and human cells, we investigated the potential of SOCE modulators drugs to improve the performance of DC- based immunotherapy in a melanoma mouse model. To this end, CD45.2 wild-type (WT) mice were inoculated with B16-OVA melanoma tumor cells, and when tumors reached an average surface of 20-25 mm2, mice were vaccinated with LPS-matured BMDCs loaded with either OT-I-L peptide (Fig.8-9) or B16-OVA tumor lysate (Tlys, Fig.10-11), and treated with SOCE-modulating drugs or DMSO-vehicle control, or unvaccinated (PBS, no cells) as a control. Mice received a second dose of the same DC-vaccine 6-7 days after the first dose, as a booster. At the endpoint, popliteal (injection draining) and inguinal (tumor draining) lymph nodes (pLN, iLN) were analyzed in a subset of mice, and tumors were collected and analyzed by two 15 to 17-color flow cytometry panels to evaluate main immune cell populations and responses. In vivo DC-vaccine of BMDCs loaded with OT-I-L peptide The administration of OT-I-L SOCE-treated DC-vaccines demonstrated enhanced tumor control compared with PBS control, with pBr additionally showing benefit compared to the DMSO group. This was reflected in slower tumor growth (Fig.8A), reduced tumor weight in the pBr treated group (Fig.8B), and significantly increased leukocyte infiltration (%CD45+ cells) within the tumor in both Tg and pBr groups (Fig.8C). From within the leukocyte (CD45+) population, a general analysis of the lymphoid T and myeloid compartments was performed, to elucidate the key players responsible for the better control of the tumor. While the fraction of total CD8 T cells was decreased in the pLN of the Tg treated group, levels in the iLN and tumor remained constant across conditions (Fig.8D). In contrast, the proportion of CD8+ T cells producing IFNG and TNFa (Fig.8Ei-ii) were strongly increased in both Tg and pBr-treated groups in the pLN, and by vaccination generally in the iLN. Within tumors, IFNG+ CD8 cells were increased in the pBr condition (Fig 8Ei). Whereas a trend towards increased density in both total (Fig 9Ai) and IFNG+ CD8 (Fig 9Aii) was observed for both Tg and pBr groups, a trend for decreased proportion (Fig 8Eii) and density (Fig 9Aiii) of TNFA+ CD8 cells was noted in DMSO and Tg but not the pBr group, though it was not significant. Conversely, cytolytic GrzB+ CD8+ cells were mainly restricted to the tumor, and while the trend for increased proportion in the SOCE-treated groups was not significant, an increased density in this cell population was noted in the pBr-treated group as compared to PBS controls (Fig.8Eiv). Additionally, a small significant increase in the proportion of CD4+FoxP3- Th cell tumor infiltration was observed, in the Tg group (Fig.8F), exhibiting a non-significant trend towards increased density in both SOCE-treated groups (Fig.9Bi). Moreover, IFNG+ CD4 Th cells (marker of Th1 phenotype) primarily localized within the tumor, where the percentage of IFNG+ cells was increased by pBr treatment (Fig.8Gi). Similar to the response observed in the CD8 T cell population, TNFA+ CD4 Th cells (associated with both Th1 and Th17 phenotypes) were significantly increased in the pLN of the SOCE-activator treated groups, and in all vaccinated groups in the iLN, whereas the trend toward increased proportion in tumors in the pBr group was not significant (Fig.8Gii). While the density of all cytokine-producing CD4 Th cells showed an increased trend in the tumor of both SOCE- treated DC-vaccinated groups, the differences were not significant (Fig.9B). Furthermore, Treg (CD4+FoxP3+) infiltration within tumors was uniformly low across all groups, whereas a slight increase in Tregs in the pLN in the DMSO but not SOCE-treated vaccine group was noted (Fig.8Hi). Although a trend towards increased Treg density (Fig.9Ci) and increased Treg proliferation (Ki67+) in the pLN (Fig 9Cii) were noted, an increased ratio of CD8 over Tregs and trend toward an increased CD4 Th to Treg ratio was observed only in SOCE- treated groups, nevertheless highlighting a positive balance in the immune response of the vaccinated mice (Fig.8Hii, iii). Finally, in the myeloid compartment a small but significant increase in the endogenous DCs (CD11c+MHC-II+) in the pLN in DMSO treated group and in both the DMSO and Tg- treated groups within the tumor (Fig.8Ii). DC subset analysis showed a significant increase in MoDCs (Ly6C+DCs) within tumors in the Tg-treated group (Fig.8Iii), whereas the proportion of cDC1 (XCR1+DCs) was decreased by SOCE treatment in the pBr group (Fig. 8Iiii). On the other hand, the fraction of proliferating cDC1s was increased in both SOCE- treated groups with respect to control and further in pBr as compared to the DMSO group in pLN, and in pBr within tumors (Fig.8Iiv). Lastly, the fraction of cDC2 (CD11b+DCs) in tumors was also increased in the pBr group (Fig.8Iv). In vivo DC-vaccine of BMDCs loaded with B16-OVA tumor lysate (Tlys) Given the promising results using the peptide-loaded DC-vaccine, a more extended analysis was performed using BMDCs loaded with Tlys, an antigen source containing a broader range of known and unknown tumor-associated antigens. A significant improvement in tumor control was observed in mice receiving both Tg or pBr-treated BMDCs loaded with Tlys, resulting in slower tumor growth compared to both control and DMSO conditions (Fig. 10A). Notably, in the absence of antigen vaccination with BMDCs showed no effect in the pBr group but worsened tumor growth in the DMSO and Tg groups compared to controls, underscoring the importance of antigen presentation in the efficacy of the DC-vaccine (Fig. 11A). Flow cytometry analysis of tumors of Tlys DC-vaccine groups revealed important differences in tumor composition. This included a decrease in tumor weight in both SOCE groups (Fig.10Bi) and reduced proliferation of CD45-negative cells (including tumor and tumor-associated cells) in DMSO and Tg groups (Fig.10Bii). This was accompanied by an increased fraction of CD45+ leukocytes in tumors across all vaccinated groups (Fig.10 Ci) and increased density in the SOCE groups as compared to DMSO, suggesting that a lower tumor volume is compensated by abundant infiltration of immune cells (Fig.10Cii). Within the lymphoid T cell compartment, though the fraction of total CD8 and CD4 T cells was unchanged (Fig.11B-C), DC-vaccination increased the density and proliferation of intra-tumoral CD8 (Fig.10Di-ii) and CD4 (Fig.10Ei-ii), where pBr treatment was further enhanced compared to DMSO. In contrast, whereas the fraction of Tregs was decreased generally by vaccination (Fig.11D), Treg tumor density and proliferation remained unchanged (Fig 10Fi-ii), resulting in an increased ratio of CD8 to Tregs only in tumors of SOCE groups (Fig.11E), and increased CD4 to Treg ratio across all vaccinated groups resulting in a positive balance of the immune response of the vaccinated mice (Fig.11F). Vaccination also increased the cytotoxic profile of the CD8 T cells in the tumors, characterized by an elevated fraction of IFNG+, TNFA+, and GrzB+ cells compared to controls, where pBr treatment also improved IFNG+ and GrzB+ levels as compared to DMSO in tumors, and of TNFA+ in iLN (Fig.10Gi-iii). Analysis of CD8 T cell exhaustion (expression of at least two markers) showed only partial increased exhaustion (LAG3+PD1+ but not Tim3+ PD1+) of CD8 cells in tumors of the pBr group (Fig.10Giv-v). Within the CD4 Th cell population, significant increases were noted in IFNG+ cells in the pLN of the DMSO group (Fig.10Hi), in TNFA+ cells in the pLN of the Tg group, and particularly in the iLN of the pBr group (Fig.10Hii). Although the fraction of TNFA+ within the tumors was smaller in the DMSO and pBr, it was not in the Tg groups, where the density of these cells was significantly increased (Fig.10Hiii). Furthermore, whereas the fraction of IL-4 (a marker of the Th2 phenotype) and IL-17A (a marker of Th17) were not significantly different, the density of IL-17A+ cells was increased in the pBr group (Fig.10Hiv-vi). Interestingly, the fraction and proliferation of NK (TCR-NKP46+) cells within tumors was significantly increased by both SOCE groups, where in the pBr group a further increase in the density, and percentage of anti-tumor GrzB+ and IFNG+ cells was observed compared to the DMSO group (Fig, 10Ii-v). In contrast, although the relative proportion of total B (CD19+) cells was decreased overall by vaccination, the density of B cells was unchanged and an activated phenotype (CD80+MHC-II+) was discerned only in the SOCE groups, with a further increase in the Tg group as compared to DMSO (Fig.10Ji-iii). In the myeloid compartment, while the relative total proportions remained unchanged, the density of DCs (CD11c+MHC-II+) was significantly increased within tumors of the SOCE groups, with a further increase in the pBr group compared to DMSO (Fig.10Ki-ii). Subset analysis revealed that in contrast to the peptide vaccine, DC subsets remained largely unchanged, except for a small increase in tumor MoDCs in the DMSO group (Fig.11Gi-iii). Similarly, the fraction of the tumor-promoting monocytic myeloid-derived suppressor cells (Ly6C+CD11b+Ly6G-, M- MDSCs) was unchanged, although the fraction of polymorphonuclear (PMN, Ly6G+) MDSCs associated with both positive and negative roles in tumor progression was slightly decreased in the pBr group (Fig.11Hi-ii). On the other hand, the fraction and density of tumor macrophages (F4 / 80+, Mφ) was significantly increased within tumors of the SOCE groups, with a further increase in the pBr group compared to DMSO (Fig.10Li-ii). In this population, increased expression of the anti-tumor M1 phenotype marker (iNOS+) cells followed a similar pattern, and it was mirrored by significant decreases in the expression of the tumor-promoting M2 phenotype (CD206+) in both SOCE groups compared to DMSO (Fig.10Liii-iv). Together, these findings show that treatment with SOCE-modulators increases the ability of antigen-loaded BMDCs to activate and target tumor recruitment of both innate and adaptive immune cells, underscoring the strong potential of SOCE-activated BMDCs for enhancing the therapeutic efficacy of DC-vaccines against B16-OVA melanoma. Discussion Overall, moderate in vitro responses of BMDCs in co-culture with CD8 T cells translated to clearly significant improvements in vivo. Given the fact that the effect of Tg observed in human cells in vitro was much larger than in mice, this provides solid argument for continued investigation of the strong potential for SOCE modulators to improve in vivo anti-tumor responses in human patients. We also provide compelling evidence that other 2APB analogs such as pI or other modulators such as palmitate show promising benefits in murine cells that warrant further investigation for their use in human cells. In light of the stronger benefit imparted by pBr treatment of murine DCs in both immunotherapy models, further characterization of the dose-dependence on antigen presentation in human cells of these alternative SOCE modulators is also of high priority. While immune checkpoint inhibitor (ICB) and adoptive T cell transfer remain preferred immunotherapy approaches, DC vaccines are gaining ground, especially when combined with other strategies. These include conventional radio / chemotherapy and tactics to optimize current DC-vaccine designs, such as approaches to enhance tumor lysate immunogenicity, activation with other cytokines or inflammatory agonists, together with approaches that increase poor lymphocyte infiltration observed in clinical trial of various DC-vaccine formulations currently under study. Since the improved tumor control correlated with increased infiltration of both innate and adaptive immune cells rather than decreased immunosuppression, this suggests that a combination of SOCE-modulator boosted DC vaccines with ICB may provide the most effective tumor control. Importantly, the DC- boosting effect of Tg and pBr translated to better tumor control that not only increased CD8 T cell responses correlated, but also with CD4 Th and B cell activation, as well as the activation and recruitment of innate immune cells including NK cells and macrophages, and to a lesser extent endogenous DCs. Together with RNAseq and cytokine array data, these observations suggest that in addition to effects on antigen processing, SOCE modulation likely improve secreted signals capable of affecting a large variety of immune cells. This also substantiates the potential for additional in vitro uses of SOCE-modulators where activation of APCs other than DCs or immune cell targets other than CD8 T cells are desired. Thus, this strategy may also be applied to different steps in the development of other immunotherapies, including both pre-clinical and clinical research uses requiring APCs, such as preparation and expansion of antigen-specific T cell clones, TILs or CAR-T cell therapies, in which in vitro / ex vivo expansion and activation of these cells could be enhanced by prior treatment of APCs with these SOCE-modulators. Example 7 - SOCE modulators boost the detection and growth of antigen specific T cells The ability to reliably detect and amplify antigen-specific T cells is essential for vaccine and immunotherapy development, yet existing methods are often limited in sensitivity, particularly when antigen immunogenicity is weak. In a pilot study, to assess whether SOCE modulators could improve detection, a highly immunogenic peptide pool derived from CMV, EBV, and influenza antigens (CEF) was tested. PBMCs were stimulated with these antigens in the presence or absence of the compounds bis-1,3-2APB in closed form (PM), bis-1,4- 2APB in closed form (PP), p-Br-2APB (pBr) or thapsigargin (Tg), and were analyzed by flow cytometry for activation induced markers (AIM). Based on prior results, it was anticipated that Tg, a strong SOCE modulator, would trigger substantial non-specific responses and therefore tested it at a single concentration for comparison. In contrast, the 2-APB derivatives (2-APB deriv.), which in general display milder or mixed modulatory activity, were evaluated across multiple concentrations to identify an optimal dose for preferential enhancement of antigen-specific responses. Tg stimulation led to large increases in the percentages of both CD8+ and CD4+ T cells expressing IL-2 and IFNG, as well as in CD4+TNFA+ T cells (Fig 12A-B). To a lesser extent it also increased the percentage of both CD4+ and CD8+ T cells expressing both IFNG and GrzB activation markers, which were not detected in the CD4+ population under control conditions, as well as the mean fluorescence intensity (MFI) of IFNG expression (Fig 12A-D). However, the stimulation was mainly non-specific. By contrast, 2-APB derivatives, in particular PM, enhanced antigen-specific responses to much milder extent but more selectively, increasing the percentages of cytokine-producing CD4⁺ and CD8⁺ T cells in a concentration-dependent manner, particularly in IL-2+ and IFNG+GrzB+ double positive cells. Together, these results indicate that SOCE modulators can amplify antigen-specific signals in standard AIM assays, with the potential to extend detection to a wider diversity of T cells responding to strongly immunogenic peptides. It was next examined whether SOCE modulators could also improve detection of T cells specific for a weakly immunogenic antigen, using the measles NP peptide pool. As expected, antigen stimulation alone produced only modest or no antigen-specific cytokine responses (Fig 13A-B). Addition of Tg markedly boosted both antigen-specific and non-specific T cells, especially within CD4⁺ subsets. In contrast, PM preferentially stimulated antigen-specific CD8+ cells, with a smaller effect on IL-2+ and TNFA+CD4+ cells. These findings suggest that SOCE modulators, particularly PM, can help unmask weak antigen-specific responses and to eventually isolate weakly responding T cells that might otherwise be undetectable using standard protocols. This enables detection of a population of cells that would otherwise remain undetectable. Finally, in addition to acute cytokine detection, we asked whether SOCE modulators could influence longer-term expansion of antigen-specific cells. PBMCs were stimulated with the immunogenic CEF peptide pool in the presence or absence of PM and monitored for growth over 14 days. In control conditions, antigen-specific T cells expanded progressively, reaching approximately 6-fold expansion after 14 days (Fig 13C). Strikingly, in the presence of PM, the same level of expansion was achieved by day 7, effectively doubling the rate of antigen-specific T cell outgrowth. These data suggest that SOCE modulators not only enhance the detection of antigen-specific responses in short-term assays but also accelerate their expansion in culture. Together, this dual effect supports their potential utility in both diagnostic and therapeutic applications where robust antigen-specific T cell responses are required. The PM compound showed preferential enhancement of antigen-specific responses, suggesting a contribution from APC-mediated mechanisms. Without wishing to be bound by theory, it is hypothesized that PM and related modulators act, at least in part, through APCs (for example by enhancing APC-mediated cytokine secretion) to potentiate antigen-specific T cell activation. A combination of both APC-dependent and T cell dependent mechanisms is also possible. PBMC isolation and culture PBMCs were isolated from buffy coat by density gradient centrifugation with lymphoprep (Axis-Shield) using leucosep tubes (Greiner), and were frozen in 45% RPMI 45% FBS, 10% DMSO. PBMCs were cultured in RPMI supplemented with 10% human AB serum, 10 mM HEPES 1% pen-strep 50 μM β-mercaptoethanol and 3000 U / ml human recombinant IL-2 (huR-10 medium). Detection of immunogenic antigen-specific T cells PBMCs were unfrozen, seeded in 96-well plates at 2 x 106cells per well, and allowed to rest for 4h at 37oC / 5%CO2. Immunogenic antigen (Ag) CEF peptide pools consisting of overlapping peptides derived from human cytomegalovirus pp65 protein (CMV), Epstein barr virus consensus peptides (EBV), and Influenza A (H1N1) HA protein (Flu), (PepTivator, Miltenyi), were added to each well at 0.5 µg / ml. After 10 min incubation at 37oC / 5%CO2, bis- 1,3-2APB in closed form (PM), bis-1,4-2APB in closed form (PP), p-Br-2APB (pBr) or thapsigargin (Tg) were added at the indicated concentrations. After 1h incubation at 37oC / 5%CO2, GolgiPlug Protein Transport Inhibitor (BD Biosciences) was added at a 1:1000 dilution, and cells were incubated overnight. For the activation induced marker (AIM) assay a multi-color flow cytometry analysis was performed. Cells were resuspended in Fc-Block (Thermo) and incubated on ice for 15 min. Cells were centrifuged and resuspended in an antibody mixture containing BUV737-anti-CD8 (#612755, BD Biosciences), AF700-anti- CD3 (#344822) and APC / Cy7-anti-CD4 (#300518, both from Biolegend), LIVE / DEAD Fixable Aqua Dead Cell Stain (1:20, #L34966, Thermo), and incubated for another 30 min. Cells were washed once in FACS Buffer (0.5% BSA, 5 mM EDTA in PBS), then fixed for 20 min, washed and permeabilized using the (#00-5523-00, eBioscience) Transcription Factor Staining kit buffers. Cells were then stained for 30 min with an antibody mixture in permeabilization buffer containing: AF700-anti-CD3, PB-anti-IFNG (#502522), BV650-anti- TNFa (#502938), PE-anti-IL-2 (#500307), and PE / Dazzle594-anti-GrzB (#372216, all from Biolegend). Washed cells were analyzed using a BD Fortessa flow cytometer. Viable T cells were identified as LIVE / DEAD Aqua negative, CD3+ cells. Detection of T cells specific for weakly immunogenic antigens PBMCs were unfrozen in medium containing 0.1 mg / ml DNAse I for 5 min, and washed. Cells were then seeded in 96-well plates at 1 x 106cells per well, and allowed to rest overnight at 37oC / 5%CO2. A peptide pool of a weakly immunogenic antigen (Ag) consisting of overlapping peptides of the measles NP protein (PepTivator, Miltenyi), was added to each well at 1 µg / ml. After 10 min incubation at 37oC / 5%CO2, bis-1,3-2APB in closed form (PM, 5 µM), or thapsigargin (Tg, 0.1 µM) were added. After 1h incubation at 37oC / 5%CO2, GolgiPlug was added as above, and cells were incubated for another 3h. The AIM assay was performed as above. Growth analysis of antigen-specific T cells PBMCs were unfrozen in medium containing 0.1 mg / ml DNAse I for 5 min, and washed. Cells were then seeded in 96-well plates at 2.5 x 106cells / ml, and allowed to rest overnight at 37oC / 5%CO2. Cells were then stimulated with the CEF peptide pool and bis-1,3- 2APB in closed form (PM) as above. After 4h, cells were transferred to a 24-well plate and diluted to 0.5 x 106cells / ml. Cells were monitored and counted and the medium refreshed every 2-3 days. Fold expansion was calculated by normalizing cells counts to the initial number of seeded cells. Flow cytometry analysis of PE / Cy7-anti-CD3 at day 14 confirmed cultures consisted of >90% T cells. Numbered further embodiments 1. A method of promoting antigen presentation in a professional antigen presenting cell (APC), comprising contacting the professional APC with an antigen and a modulator of store- operated calcium entry (SOCE). 2. The method of embodiment 1, wherein the professional APC is contacted with the antigen before contacting the professional APC with the modulator of SOCE. 3. The method of embodiment 1 or 2, wherein the steps of contacting the professional APC with an antigen and / or contacting the professional APC with a modulator of SOCE are performed in the absence of T cells. 4. The method of any one of the preceding embodiments, wherein the modulator of SOCE is selected from the group consisting of (i) thapsigargin, (ii) 2-aminoethyl diphenylborinate (2APB) or a derivative thereof, such as p-Br-2APB or p-I-2APB, and (iii) palmitate. 5. The method of any one of the preceding embodiments, wherein antigen presentation is increased by at least 10 % when compared to an otherwise identical method that does not involve the modulator of SOCE. 6. The method of any one of the preceding embodiments, wherein the method further comprises contacting the professional APC with a molecule that stimulates ceramide production, optionally wherein the molecule comprises a palmitoyl moiety and / or the modulator of SOCE comprises the molecule that stimulates ceramide production. 7. A method of activating an immune cell, wherein the method comprises: performing the method of any one of the preceding embodiments, to thereby produce an antigen-loaded professional APC; and contacting the antigen-loaded professional APC with the immune cell. 8. A method of activating a population of T cells specific for an antigen, wherein the method comprises: performing the method of any one of embodiments 1 to 6, to thereby produce an antigen-loaded professional APC; contacting the antigen-loaded professional APC with a population of T cells. 9. The method of embodiment 7 or 8, wherein the method further comprises a step of washing the antigen-loaded professional APC to remove the modulator of SOCE and / or the antigen before contacting the antigen-loaded professional APC with the immune cell or population of T cells. 10. The method of any one of embodiments 7 to 9, wherein: the immune cell is a T cell, optionally wherein the T cell is a CD8+T cell; or the population of T cells is a population of CD8+T cells. 11. The method of any one of the preceding embodiments, wherein: the professional APC is a dendritic cell; the professional APC is a bone marrow-derived cell or a peripheral blood mononuclear cell-derived cell; the professional APC is not genetically-modified; the professional APC, the immune cell and / or the population of T cells are human cells or non-human mammalian cells, such as mouse cells. 12. A professional APC obtained or obtainable by the method of any one of embodiments 1 to 6 or 11, an immune cell obtained or obtainable by the method of any one of embodiments 7 and 9 to 11, or a population of T cells obtained or obtainable by the method of any one of embodiments 8 to 11. 13. A pharmaceutical composition comprising the professional APC obtained or obtainable by the method of any one of embodiments 1 to 6 or 11, or an immune cell obtained or obtainable by the method of any one of embodiments 7 and 9 to 11, or a population of T cells obtained or obtainable by the method of any one of embodiments 8 to 11. 14. The pharmaceutical composition of embodiment 13 for use in a method of treating a disease in a subject. 15. A method of treating a disease in a subject, the method comprising administering the pharmaceutical composition of embodiment 13 to the subject. 16. A method of treating a disease in a subject, the method comprising: contacting a professional APC with an antigen and a modulator of store-operated calcium entry (SOCE) to thereby produce an antigen-loaded professional APC, and administering the antigen-loaded professional APC to the subject; or contacting a professional APC with an antigen and a modulator of store-operated calcium entry (SOCE) to thereby produce an antigen-loaded professional APC, contacting the antigen-loaded professional APC with an immune cell or a population of T cells to thereby produce an activated T cell or a population of activated T cells, and administering the activated T cell or population of activated T cells to the subject. 17. The pharmaceutical composition for use according to embodiment 14, or the method of embodiment 15 or 16, wherein the disease is cancer. 18. Use of a modulator of store-operated calcium entry (SOCE) for promoting antigen presentation in a professional APC. 19. The compounds p-I-2APB in open form, bis-m-Br-2APB, bis-1,3-2APB in closed form, bis-1,4-2APB in closed form, and 2-aminohexadecanoic acid-p-Br-2APB.

Claims

CLAIMS 1. A method of promoting antigen presentation in a professional antigen presenting cell (APC), comprising contacting the professional APC with an antigen and a modulator of store- operated calcium entry (SOCE).

2. The method of claim 1, wherein the professional APC is contacted with the antigen before contacting the professional APC with the modulator of SOCE.

3. The method of claim 1 or 2, wherein the steps of contacting the professional APC with an antigen and / or contacting the professional APC with a modulator of SOCE are performed in the absence of T cells.

4. The method of claim 1 or 2, wherein the steps of contacting the professional APC with an antigen and / or contacting the professional APC with a modulator of SOCE are performed in the presence of T cells.

5. The method of any one of the preceding claims, wherein the modulator of SOCE is selected from the group consisting of (i) a derivative of 2-aminoethyl diphenylborinate (2APB) such as bis-1,3-2APB (e.g. in closed form), bis-1,4-2APB (e.g. closed form), as p-Br- 2APB or p-I-2APB, (ii) thapsigargin, (iii) 2APB, and (iii) palmitate.

6. The method of any one of the preceding claims, wherein antigen presentation is increased by at least 10 % when compared to an otherwise identical method that does not involve the modulator of SOCE.

7. The method of any one of the preceding claims, wherein the method further comprises contacting the professional APC with a molecule that stimulates ceramide production, optionally wherein the molecule comprises a palmitoyl moiety and / or the modulator of SOCE comprises the molecule that stimulates ceramide production.

8. A method of activating an immune cell, wherein the method comprises:performing the method of any one of the preceding claims, to thereby produce an antigen-loaded professional APC; and contacting the antigen-loaded professional APC with the immune cell.

9. A method of activating a population of T cells specific for an antigen, wherein the method comprises: performing the method of any one of claims 1 to 6, to thereby produce an antigen- loaded professional APC; contacting the antigen-loaded professional APC with a population of T cells.

10. The method of claim 8 or 9, wherein the method further comprises a step of washing the antigen-loaded professional APC to remove the modulator of SOCE and / or the antigen before contacting the antigen-loaded professional APC with the immune cell or population of T cells.

11. The method of claim 8 or 9, wherein the professional APC is loaded with antigen at the same time as contacting the professional APC with the immune cell or population of T cells.

12. The method of any one of the preceding claims, wherein: the professional APC is a dendritic cell; the professional APC is a bone marrow-derived cell or a peripheral blood mononuclear cell-derived cell; the professional APC is not genetically-modified; the professional APC, the immune cell and / or the population of T cells are human cells or non-human mammalian cells, such as mouse cells.

13. A method of activating an immune cell, wherein the method comprises contacting the immune cell with a modulator of store-operated calcium entry (SOCE), wherein the modulator of SOCE is selected from the group consisting of (i) a derivative of 2-aminoethyl diphenylborinate (2APB) such as bis-1,3-2APB (e.g. in closed form), bis-1,4-2APB (e.g. closed form), as p-Br-2APB or p-I-2APB, and (ii) 2APB.

14. The method of any one of claims 8 to 13, wherein:the immune cell is a tumour infiltrating lymphocyte and / or the immune cell is a T cell, optionally wherein the T cell is a CD8+T cell; or the population of T cells is a population of tumour infiltrating lymphocytes and / or CD8+T cells.

15. A professional APC obtained or obtainable by the method of any one of claims 1 to 7 and 12, an immune cell obtained or obtainable by the method of any one of claims 8 and 10 to 14, or a population of T cells obtained or obtainable by the method of any one of claims 9 to 12 and 14.

16. A pharmaceutical composition comprising the professional APC obtained or obtainable by the method of any one of claims 1 to 7 and 12, an immune cell obtained or obtainable by the method of any one of claims 8 and 10 to 14, or a population of T cells obtained or obtainable by the method of any one of claims 9 to 12 and 14.

17. The pharmaceutical composition of claim 16 for use in a method of treating a disease in a subject.

18. A method of treating a disease in a subject, the method comprising administering the pharmaceutical composition of claim 16 to the subject.

19. A method of treating a disease in a subject, the method comprising: contacting a professional APC with an antigen and a modulator of store-operated calcium entry (SOCE) to thereby produce an antigen-loaded professional APC, and administering the antigen-loaded professional APC to the subject; or contacting a professional APC with an antigen and a modulator of store-operated calcium entry (SOCE) to thereby produce an antigen-loaded professional APC, contacting the antigen-loaded professional APC with an immune cell or a population of T cells to thereby produce an activated T cell or a population of activated T cells, and administering the activated T cell or population of activated T cells to the subject.

20. The pharmaceutical composition for use according to claim 17, or the method of claim 18 or 19, wherein the disease is cancer.

21. Use of a modulator of store-operated calcium entry (SOCE) for promoting antigen presentation in a professional APC.

22. The compounds bis-1,3-2APB in closed form, bis-1,4-2APB in closed form, p-I-2APB in open form, bis-m-Br-2APB, and 2-aminohexadecanoic acid-p-Br-2APB.

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