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Application of RGS1 as target spot in adoptive cellular immunotherapy of tumors

A cellular immunity and adoptive technology, applied in antitumor drugs, animal cells, vertebrate cells, etc., can solve the problem that lymphocytes cannot reach tumors, and achieves improved anti-tumor effect, improved tumor treatment effect, and induced tumor cell apoptosis. the effect of death

Pending Publication Date: 2022-06-21
SUN YAT SEN MEMORIAL HOSPITAL SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Therefore, the existing technology urgently needs corresponding targets or treatment methods to make up for the limitations of ACT treatment strategies in the prior art, and at the same time, to overcome the problem that lymphocytes with tumor killing function cannot reach the local tumor to infiltrate and exert tumor killing effect This problem can improve the effect of tumor immunotherapy

Method used

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  • Application of RGS1 as target spot in adoptive cellular immunotherapy of tumors
  • Application of RGS1 as target spot in adoptive cellular immunotherapy of tumors
  • Application of RGS1 as target spot in adoptive cellular immunotherapy of tumors

Examples

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Effect test

Embodiment 1

[0085] (1) The expression of RGS1 is related to the weakened recruitment ability of Th1 cells and CTL to breast cancer tissue

[0086] It has been reported that the intracellular signal transduction of G protein-coupled receptors of chemokines that control immune cell trafficking is checked by a group of G protein signal transduction regulators (RGS), but this type of RGS is detected in various human T cells. Expression in cell subpopulations has not yet been elucidated. In order to further explore whether the expression of RGS affects the recruitment of tumor T cells in breast cancer patients, this example uses the qRT-PCR method to compare the expression of RGS1 in Th1 cells isolated from primary tumor tissues of breast cancer patients with high or low Th1 infiltration situation, the result is as figure 2 As shown in A. A similar situation exists for infiltrating effector cell CTLs, such as figure 2 As shown in A. That is, the expression level of RGS1 is higher in Th1 ...

Embodiment 2

[0089] To further evaluate the clinical significance of RGS1, we investigated the expression of RGS1 in peripheral blood (PB) T cells of breast cancer patients. RGS1 expression of Th1 cells and effector CTLs in the peripheral blood of 219 breast cancer patients was correlated with clinical immunological characteristics of the patients. The optimal cut point of RGS1 expression in circulation effect CTL was determined by qRT-PCR and X-tile analysis (relative to GAPDH normalization, ≤0.01 was low expression, >0.01 was high expression), and high RGS1 expression in circulation effect CTL was associated with greater Tumors, more lymph node metastases, higher tumor cell proliferation and less apoptosis were associated, but not with patient age, pathological grade, and molecular subtype of breast cancer. Similarly, patients with higher RGS1 expression in circulating Th1 cells had larger tumor size and less tumor cell apoptosis, but expression was independent of tumor molecular subtype...

Embodiment 3

[0100] RGS1 inhibits intracellular signaling mediated by G protein-coupled receptors (GPCRs)

[0101] The RGS family is a class of proteins that interact with G proteins and inhibit G protein signaling by accelerating the activity of intracellular GTPases. In this example, it was investigated whether RGS1 affects the chemotaxis of Th1 and effector CTLs by inhibiting the downstream signaling of chemokine receptors.

[0102] The results of co-immunoprecipitation showed (such as Figure 4 A), RGS1 specifically binds CCR4, CXCR4, and CXCR3, but not CCR5, in effector CTLs, suggesting that RGS1 can regulate the downstream signaling of CCR4, CXCR4, and CXCR3. Furthermore, silencing of RGS1 in effector CTLs suppressed cAMP elevation following treatment with CXCL12, CCL22, or CXCL9 / 10 / 11 (eg, Figure 4 B), and enhanced calcium influx after CXCL12 stimulation (as shown in Figure 4 C shown). Meanwhile, silencing RGS1 significantly enhanced the phosphorylation of ERK and AKT in CXCL1...

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Abstract

The invention discloses an application of an RGS1 gene as an immune intracellular drug inhibition target in preparation of a tumor adoptive cellular immunotherapy drug. The invention discloses a negative regulation effect of RGS1 gene overexpression on immune cell infiltration tumors, RGS1 is taken as an inhibition target, RGS1 expression is inhibited so as to promote infiltration of T cells with a tumor killing function or promote tumor killing function, and the problem that tumor specific T cells in a tumor microenvironment are difficult to infiltrate or survive is solved. The T cells inhibiting RGS1 expression can be amplified in vitro to improve the adoptive cellular immunotherapy effect, and the medicine is expected to directly act on the T cells in the body to inhibit the RGS1 expression of the T cells and improve the anti-tumor effect of the autoimmune system. The polypeptide can be combined with RGS1 inhibition and immune checkpoint inhibition to realize a more significant anti-tumor effect, provides a new treatment scheme for tumor treatment, and is applied to clinical treatment to improve the tumor treatment effect and the survival rate of patients.

Description

technical field [0001] The present invention relates to the field of immunotherapy, and more specifically, relates to a use of RGS1 as a target in adoptive cellular immunotherapy of tumors. Background technique [0002] Adoptive Cell Transfer Therapy (ACT) refers to the isolation of immunocompetent cells from tumor patients, expansion and functional identification in vitro, and then reinfusion to patients, so as to directly kill tumors or stimulate the body's immune response A method of killing tumor cells to achieve therapeutic purposes. This type of method has achieved good therapeutic effects in clinical trials of some solid tumors and blood cancers in recent years, and is a widely used immunotherapy method in clinical treatment. [0003] At present, ACT treatment strategies in clinical application mainly include tumor infiltrating lymphocyte (tumorinfiltrating lymphocyte, TIL) therapy, T-cell receptor (T-cell receptor, TCR) therapy and chimeric antigen receptor (chimeri...

Claims

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Application Information

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IPC IPC(8): C12Q1/6886C12N5/10C12N15/867A61K35/17A61P35/00
CPCC12Q1/6886C12N5/0636C12N15/86A61K35/17A61P35/00C12Q2600/158C12N2510/00C12N2740/10043
Inventor 宋尔卫苏士成黄迪陈雪曼
Owner SUN YAT SEN MEMORIAL HOSPITAL SUN YAT SEN UNIV
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