Compound for use in the prevention and / or treatment of cancer

Abstract

The present belongs to the field of disease therapy, and more specifically to the field of cancer therapy. It relates more specifically to compound activating the peroxisome proliferator-activated gamma receptor (PPARγ) for use in the prevention and / or treatment of cancer involving small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM). It also relates to a pharmaceutical composition comprising at least one compound activating the peroxisome proliferator-activated gamma receptor (PPARγ) for use in the prevention and / or treatment of cancer.

Description

[0001] Compound for use in the prevention and / or treatment of cancer

[0002] Technical field

[0003] The present invention belongs to the field of disease therapy, and more specifically to the field of cancer therapy. It relates more specifically to compound activating the peroxisome proliferator-activated gamma receptor (PPARy) for use in the prevention and / or treatment of cancer involving small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM).

[0004] In the description below, references between [ ] refer to the list of references at the end of the examples.

[0005] Technical background

[0006] Ovarian adenocarcinoma represents the leading cause of cancer mortality in women with gynecological malignancy. Its poor prognosis is mainly due to the fact that sixty percent of women who are diagnosed with ovarian cancer present an extensive peritoneal carcinomatosis and despite efficient surgery and chemotherapy, most patients with advanced-stage ovarian cancer relapse within 12-18 months [Khazaei et al, 2021 ], Treatments for women with ovarian cancer (platinum salts, taxanes) have not evolved for many decades. The recent introduction of Poly-ADP Ribose Polymerase (PARP) inhibitors into the treatment plan and the evolution of surgical techniques have increased the 5-year survival rate [Sopik et al, 2015], However, it remains at less than 50% to date and patients succumb to recurrent chemo-resistant disease.

[0007] There is therefore a real need to find a method and / or a compound which allows more efficient treatment and / or effective treatment of cancer, in particular ovarian cancer. There is also a real need to find a method and / or a compound which allows more efficient treatment and / or effective treatment of ovarian adenocarcinoma.

[0008] As in many cancers, a chronic non-resolving inflammation at the site of the ovarian epithelium is associated with ovarian cancer risk [Cuesta et al, 1996 ; Ness et al 2000 ; Risch et al, 1995], When the tumor has grown, in parallel with local inflammation at the site of the ovarian epithelium, tumor ascites, which are a reservoir of a complex mixture of soluble factors and cellular components, provide a pro-inflammatory and tumor-promoting microenvironment in the peritoneal cavity [Ahmed et al, 2013], The ascites fluid as been disclosed as promoting the tumorigenesis and the acquisition of cancer cell chemoresistance through a macrophage-dependent mechanism [Le Naour, 2020],

[0009] There is therefore a real need to find a method and / or a compound which allows more efficient treatment and / or effective treatment of cancer involving tumor ascites and / or ascites fluid.

[0010] Indeed, among the cellular microenvironment, tumor-associated macrophages (TAMs) represent the most abundant infiltrating immune population in human ovarian tumors and ascites [Wang et al, 2006], Through their plasticity, macrophages can exert a critical role in the orientation of the inflammatory response and hence in tumor development. In established tumors, TAMs produce growth factors (e.g. Epithelial Growth factor (EGF)), angiogenic factors (e.g. Vascular Endothelial Growth Factor (VEGF)) and proteases (e.g. Matrix Metalloproteinases-9 (MMP-9)) hence favoring tumor cell proliferation and survival, angiogenesis, and metastasis [Chanmee et am, 2014 ; Lewis et al, 2006], In addition, these TAMs exhibit potent anti-inflammatory and immunosuppressive functions. Indeed, they have poor ability to present tumor- associated antigens because of a downregulation of the expression of MHCII (Major Histocompatibility Complex II) molecules [Elgert et al, 1998], Moreover, they directly prevent T-cell activation by production of immunosuppressive factors (e.g. IL-10 (lnterleukine-10) and TGF-[3 (Transforming Growth Factor)) and upregulation of co-signaling pathways, called immune checkpoints, that suppress T-cell receptor signal (e.g. PDL-1 (Programmed Death Ligand-1 ), PDL-2 and CTLA-4 (Cytotoxic T Lymphocytes Antigen 4) ligand) [Chanmee et al, 2014 ; Sharma et al, 2015], TAMs can also suppress CD4+and CD8+T-cell effector function indirectly by recruitment of natural regulatory T cells (Tregs) via CCL17 (C-C motif chemokine Ligand-17) and CCL22 production [Noy et al, 2014], Moreover, the pro-inflammatory macrophages described to be involved in antitumor immunity through their capacity to release pro-inflammatory cytokines, reactive nitrogen and oxygen intermediates, can also enhance neoplastic transformation, immunosuppression and metastatic potential in several cancers including ovarian adenocarcinoma [Biswas et al, 2008 ; Cho et al, 2018 ; Robinson-Smith et al, 2007 ; Van Ginderachte et al, 2006], highlighting the relevance to develop TAM-targeting therapy in cancer.

[0011] There is therefore a real need to find a method and / or a compound which allows an efficient treatment and / or effective treatment of cancer involving microenvironment, tumor-associated macrophages, for example by reducing their capacity to favor tumor cell proliferation and survival, angiogenesis, and metastasis .

[0012] A growing number of studies evidenced that TAMs complexity and heterogeneity not only depend on their activation status but also on their ontogeny [Kiss et al, 2018 ; Van Overmeire et al, 2014], Indeed, although peripheral blood monocytes were long thought to be obligatory intermediates in the differentiation of tissue macrophages, studies demonstrated that several organ-resident macrophages had an embryogenic origin [Van Overmeire et al, 2014], Thus, cavity macrophages were derived from primitive precursors and were self-maintained locally under steady-state without a significant input from circulating monocytes [Ginhoux et al, 2010 ; Hashimoto et al, 2013 ; Yona et al, 2013], In situations that deviate from the steady-state, as in cancer, several macrophage populations of different origins can coexist in tissues. In the peritoneal cavity two physically, functionally and developmentally distinct peritoneal macrophage subsets, called large peritoneal macrophages (LPM) and small peritoneal macrophages (SPM), coexist [Ghosn et al, 2010).]. While LPM (F4 / 80high, CD11 bhigh, MHCII|OW) (class II molecules of the major histocompatibility complex (MHCII)) represent the most abundant subset under steady state conditions and appear to be originated from embryogenic precursors, SPM (F4 / 80|OW, CD11 bl0W, MHCIIhigh) are generated from bone-marrow myeloid precursors and become the prevalent population in inflammatory conditions [Cassado et al, 2015], After inflammatory or infectious stimuli, the increase of SPM population is accompanied by LPM disappearance also called Macrophage Disappearance Reaction (MDR) [Barth et al, 2010], This LPM disappearance is associated to the LPM migration into the omentum due to the diminution of GATA6 expression, a major transcription factor involved in the emergence of peritoneal macrophage identity [Okabe et al, 2014], In situation where LPM pool was greatly reduced, such as in inflammatory conditions, it has been shown that SPM differentiate into LPM, hence participating to the maintenance of LPM in the peritoneal cavity [Cain et al, 2013],

[0013] In tumor context, Rei and al. demonstrated in a murine model of ovarian cancer that SPM mobilization in response to IL-17 is associated with tumor progression [Rei et al, 2014], SPM were strikingly enriched in pro- inflammatory / proangiogenic factors which participate to the ovarian cancer cell proliferation [Rei et al, 2014], This study highlights for the first time the protumor activity of SPM subset. Thus, these data suggest that the differentiation of protumor SPM towards LPM, described to be involved in the maintenance of peritoneal cavity homeostasis, could decrease tumor progression.

[0014] There is therefore a real need to find a method and / or a compound which allows to the treatment of cancer, for example by inhibiting the immunosuppression in the tumor microenvironment.

[0015] There is therefore a real need to find a method and / or a compound which allows to the treatment of cancer involving small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM).

[0016] Description of the invention

[0017] The present invention allows to overcome the drawback and inconvenient of the prior art by providing a compound activating the peroxisome proliferator- activated gamma receptor (PPARy) for use in the prevention and / or treatment of cancer, in particular involving small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM).

[0018] An object of the invention is a compound activating the peroxisome prol iterator-activated gamma receptor (PPARy) for use in the prevention and / or treatment of cancer involving small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM).

[0019] The inventors have surprisingly and unexpectedly demonstrated that compounds activating the peroxisome prol iterator-activated gamma receptor (PPARy) allow surprisingly and unexpectedly to counteract cancer immunosuppression and advantageously increase the number of immunocompetent cells present in tumor and / or cancer tissue. The inventors have also surprisingly and unexpectedly demonstrated that compounds activating the peroxisome prol iterator-activated gamma receptor (PPARy) allow, in cancer involving small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM), surprisingly and unexpectedly to promote the differentiation of SPM to LPM by increasing the transition of SPM towards LPM increasing therefore the number of immunocompetent cells and a decrease the number of immunosuppressive cells.

[0020] The inventors have further surprisingly and unexpectedly demonstrated that compounds activating the peroxisome prol iterator-activated gamma receptor (PPARy) allow, in cancer involving small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM), restore LPM / SPM ratio closed to steady state conditions.

[0021] The inventors have in addition surprisingly and unexpectedly demonstrated that compounds activating the peroxisome proliferator-activated gamma receptor (PPARy) allow surprisingly and unexpectedly inhibit LPM migration from the peritoneum toward the omentum directly impacting the SPM / LPM balance that allows LPM maintenance in the peritoneum.

[0022] The inventors have in addition surprisingly and unexpectedly demonstrated that compounds activating the peroxisome proliferator-activated gamma receptor (PPARy) allow surprisingly and unexpectedly in a murine experimental model of ovarian peritoneal carcinomatosis the inhibition of tumor’s development.

[0023] The inventors have also unexpectedly demonstrated a pharmacological treatment of cancer, for example ovarian cancer, in particular ovarian carcinosis, with a compound activating the peroxisome proliferator-activated gamma receptor (PPARy).

[0024] Definitions

[0025] To facilitate an understanding of the present invention, a number of terms and phrases are defined below:

[0026] As used herein other than the claims, the terms "a," "an," "the," and / or "said" means one or more. As used herein in the claim(s), when used in conjunction with the words "comprise," "comprises" and / or "comprising," the words "a," "an," "the," and / or "said" may mean one or more than one. As used herein and in the claims, the terms "having," "has," "is," "have," "including," "includes," and / or "include" has the same meaning as "comprising," "comprises," and "comprise." As used herein and in the claims "another" may mean at least a second or more. As used herein and in the claims, "about" refers to any inherent measurement error or a rounding of digits for a value (e.g., a measured value, calculated value such as a ratio), and thus the term "about" may be used with any value and / or range.

[0027] The phrase "a combination thereof" "a mixture thereof" and such like following a listing, the use of "and / or" as part of a listing, a listing in a table, the use of "etc." as part of a listing, the phrase "such as," and / or a listing within brackets with "e.g.," or i.e. , refers to any combination (e.g., any sub-set) of a set of listed components, and combinations and / or mixtures of related species and / or embodiments described herein though not directly placed in such a listing are also contemplated. Such related and / or like genera(s), sub-genera(s), specie(s), and / or embodiment(s) described herein are contemplated both in the form of an individual component that may be claimed, as well as a mixture and / or a combination that may be described in the claims as "at least one selected from," "a mixture thereof" and / or "a combination thereof."

[0028] As used herein, the term “and / or” means any one of the items, any combination of the items, or all of the items with which this term is associated.

[0029] As used herein, the term “about” refers to a variation of ±5-10% of the value specified. For example, "about 50" percent can in some embodiments carry a variation from 45 to 55 percent. For integer ranges, the term "about" can include one or two integers greater than and / or less than a recited integer. Unless indicated otherwise herein, the term "about" is intended to include values, e.g., weight percents, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment.

[0030] As will be understood by the skilled artisan, all numbers, including those expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term "about." These values can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the descriptions herein. It is also understood that such values inherently contain variability necessarily resulting from the standard deviations found in their respective testing measurements.

[0031] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass any and all possible subranges and combinations of subranges thereof, as well as the individual values making up the range, particularly integer values. A recited range (e.g., weight percents) includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.

[0032] As will also be understood by one skilled in the art, all language such as "up to," "at least," "greater than," "less than," "more than," "or more," and the like, include the number recited and such terms refer to ranges that can be subsequently broken down into subranges as discussed above. In the same manner, all ratios recited herein also include all sub-ratios falling within the broader ratio

[0033] An "effective amount" refers to an amount effective to treat a disease, disorder, and / or condition, or to bring about a recited effect. For example, an amount effective can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art. The term "effective amount" is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host. Thus, an "effective amount" generally means an amount that provides the desired effect.

[0034] The terms "treating", "treat" and "treatment" include (i) preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and / or (iv) diminishing symptoms associated with the disease, pathologic or medical condition. Thus, the terms "treat", "treatment", and "treating" extend to prophylaxis and include prevent, prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated. As such, the term "treatment" includes medical, therapeutic, and / or prophylactic administration, as appropriate.

[0035] Peroxisome proliferator-activated gamma receptor (PPARy) refers to a member of a family of ligand-activated nuclear transcription factors which, after ligand binding, form a heterodimer with the retinoic X receptor. This heterodimer settles then to PPAR-responsive elements (PPREs) in the promoter regions of target genes. This nuclear receptor has been linked to the regulation of adipogenesis and to the maintenance of glucose and lipid metabolisms. It also controls the inflammation response through the regulation of myeloid cells activation / differentiation. [Heikkinen et al, 2007],

[0036] Monocyte-derived macrophage, also designated as Small Peritoneal Macrophages (SPM) refers to macrophages, for example which are present in the peritoneal cavity, having a F4 / 80|OW(EGF-like module-containing mucin-like hormone receptor-like 1 ) and / or CD11 bl0W(Integrin alpha M) and / or MHCII / HLADrhigh(major histocompatibility complex class II), and / or CD14high(cluster of differentiation 14), and / or CD16|OW(cluster of differentiation 16) phenotype, preferably CD14high, CD16|OWand CD11 blowphenotype. It may be for example cells generate from bone-marrow-derived myeloid precursors.

[0037] Long-lived resident macrophage, also designated as Large Peritoneal Macrophages (LPM) refers to macrophages, for example which are present in the peritoneal cavity, having a F4 / 80high, and / or CD11 bhigh, and / or MHCII|OWand / or CD14high, and / or CD16highphenotype, preferably CD11 bhigh, CD14highand CD16highphenotype. It may be for example cells originate from embryogenic precursors.

[0038] In other words, small peritoneal macrophages (SPM) refers to macrophages which express low levels of at least F4 / 80 and CD11 b and CD16 and high level of at least MHCII and CD14.

[0039] In other words, large peritoneal macrophages (LPM) refers to macrophages which express high levels of at least F4 / 80 and CD11 b and CD14 and CD16. and low level of at least MHCII The high or low level of biomarkers may be determined by known method, in particular method well known by the man with classic skill in the art. It may be for example a method as disclosed in Yu et al, 2016. It may be for example a flow cytometric analysis, for example of macrophages. It may be for example a flow cytometric analysis of macrophages from a biological sample, for example a biological sample from peritoneal fluid, with a standardized gating strategy [Yu et al, 2016], It may be for example a flow cytometric analysis of macrophages from a biological sample, for example a biological sample from peritoneal fluid, with a standardized gating strategy [Yu et al, 2016] based on relative surface expression of with biological markers, for example F4 / 80high, and / or CD11 bhigh, and / or MHCII|OWand / or CD14high, and / or CD16high. For example, according to the expression pattern of membrane markers CD14 and CD16, macrophage may be distributed into two different subpopulations in terms of CD14 and CD16 expression, CD14highand CD16highfor LPM and CD14highand CD16|OWfor SPM.

[0040] As used herein, the term CD16|OWmeans also CD16’ our CD16+, the term CD16highmeans also CD16++.

[0041] As used herein the term CD14|OWmeans also CD14 the term CD14highmeans also CD14interor CD14+ or CD14++.

[0042] Small peritoneal macrophages (SPM) refer for example to macrophage which express a low level of F4 / 80 and CD11 b and CD16 and high level of MHCII and CD14, for example a macrophage which express a low level of F4 / 80 (Adgrel ), CD11 b (Itgam), CD80, 12 / 15-lox (Alox15) and a high level of MHCII (Cd74), DC-SIGN (Cd209b),Dectin-1 (Clec7a), CD14 (cd14) and CD16 (cd16).

[0043] Large peritoneal macrophages (LPM) refers for example to macrophage which express a high level of F4 / 80, CD11 b and CD14 and CD16 and low level of MHCII, for example a macrophage which express a high level of F4 / 80 (Adgrel ), CD11 b (Itgam), CD80, 12 / 15-lox (Aloxl 5) and CD14 (cd14), and CD16 (cd16).and a low level of MHCII (Cd74), DC-SIGN (Cd209b) Dectin-1 (Clec7a).

[0044] In the present the determination of “level of expression comprises for example the identification, for example from a biological sample, of the total living macrophage based on the exclusion of a Live / Dead dye and then the evaluation by flow cytometry after staining with appropriate biomarkers. The level of expression may be determined by comparison of expression of at least one biomarker between cells. In other words, the level of expression of a biomarker for a cell may be determined in comparison with its level of expression in other cells For example small peritoneal macrophages (SPM) may be distinguished / identified in a population of macrophages with a relative high level of expression of MHCII (Cd74), DC-SIGN (Cd209b),Dectin-1 (Clec7a), CD14 (cd14) whereas large peritoneal macrophages (LPM) may distinguished / identified with a relative high level of expression of F4 / 80 (Adgrel ), CD1 1 b (Itgam), CD80, 12 / 15-lox (Aloxl 5) and CD14 (cd14) and CD16 (cd16).

[0045] In the present, activating the peroxisome prol iterator-activated gamma receptor (PPARy) means activating the peroxisome proliferator-activated gamma receptor (PPARy) formation and / or function. The terms "activation of", "to activate", "activating" or "activated" proliferator-activated gamma receptor (PPARy) formation mean that the formation of proliferator-activated gamma receptor (PPARy) is accelerated, increase or, preferably, entirely activated in the presence of the activating compound, “activating the peroxisome proliferator- activated gamma receptor (PPARy)” also means completely or partially activating the biological activity of activating the peroxisome proliferator-activated gamma receptor (PPARy) by any mode of action, including but not limited to activate the expression product of peroxisome proliferator-activated gamma receptor (PPARy) gene from being produced (activating the peroxisome proliferator- activated gamma receptor (PPARy) gene transcription and / or increasing the translation of the mRNA coming from the peroxisome proliferator-activated gamma receptor (PPARy) gene expression) and directly activating the peroxisome proliferator-activated gamma receptor (PPARy) biological activity, for example, and among others, by binding to the receptor.

[0046] In the present, a compound activating the peroxisome proliferator-activated gamma receptor (PPARy) may be any compound known from one skilled in the art and / or commercially available adapted to activate the peroxisome proliferator- activated gamma receptor (PPARy). For example, compound activating the peroxisome proliferator-activated gamma receptor (PPARy) activates its biological function. Compound activating the peroxisome proliferator-activated gamma receptor (PPARy) refers herein to any activator, agonist of PPARy that is likely to increase or to active reversibly or irreversibly, selectively or not selectively, the biological normal effect of PPARy. More particularly, it may refer to any agonist of PPARy, that is likely to bind, reversibly or irreversibly, PPARy, thereby increasing or activating, reversibly or irreversibly, the biological normal effect of PPARy. By “activate” or “activating” by an agonist it is understood a increase of at least 20%, for example 50%, 60%, 70%, 80%, 90% or 99%, of the biological effect of PPARy compared to the normal biological effect of PPARy receptor, i.e. the biological effect of PPARy receptor that is not activated by the activating compound.

[0047] Compound activating the peroxisome proliferator-activated gamma receptor (PPARy) may be for example an agonist, a partial agonist.

[0048] Compound activating the peroxisome proliferator-activated gamma receptor (PPARy) may be any compound whatever its form. It may be for example a chemical compound, a peptide, a polynucleic acid, an antibody, a nanobody.

[0049] In the present, the term “peptide” refers to a linear molecule which is formed by the manner in which the amino acid residues bind together by a peptide bond.

[0050] In the present, the term “polynucleic acid” refers to polymers of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetic thereof including those composed of naturally-occurring nucleobases, sugars and covalent internucleoside (backbone) linkages including linked poly-heterocyclic bases having non-naturally-occurring portions that function similarly.

[0051] The term "antibody" is used herein in the broadest sense. According to the present invention, "antibody" refers to any polypeptide which at least comprises (i) a Fc region and (ii) a binding polypeptide domain derived from a variable domain of an immunoglobulin. The said binding polypeptide domain is able to bind specifically one given target antigen or a group of target antigens. In the present, the antibody according to the invention has a binding affinity to peroxisome proliferator-activated receptors gamma (PPARy).

[0052] The term "nanobody" is used herein in the broadest sense according to the present invention “nanobody” refer to an antibody fragment consisting of a single monomeric variable antibody domain.

[0053] A binding polypeptide domain which derives from a variable region of an immunoglobulin comprises at least one or more CDRs. Herein, antibodies include, but are not limited to, full-length immunoglobulins, monoclonal antibodies, a VHH domain (also named single heavy chain domain or Nanobody®), multi-specific antibodies, Fc-fusion protein comprising at least one variable region, synthetic antibodies (sometimes referred to herein as "antibody mimetics"), chimeric antibodies. Antibodies also encompass antibody-fusion proteins, antibody conjugates and fragments of each respectively. Accordingly, a variant antibody of the invention comprises, in its Fc region, at least one amino acid modification that increase its binding affinity as compared to its parent antibody. Of particular interest are antibody variants which have increased in vivo half-lives as compared to parent polypeptides.

[0054] Monoclonal antibodies can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, and phage display technologies, or a combination thereof. For example, monoclonal antibodies can be produced using hybridoma techniques including those known in the art and taught.

[0055] The term "monoclonal antibody" as used herein is not limited to antibodies produced through hybridoma technology, and refers to an antibody that may be derived from a single B cell, a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.

[0056] Methods for producing and screening for specific antibodies using hybridoma technology are routine and well known in the art. In a non-limiting example, mice can be immunized with an antigen of interest or a cell expressing such an antigen.

[0057] Covalent modifications of antibodies are also included within the scope of this invention, and are generally, but not always, done post-translationally. Such modifications include, but are not limited to, glycosylates, labelling and conjugation. The term "labeling group" means any detectable label, which is a compound and / or element that can be detected due to its specific functional properties, and / or chemical characteristics, the use of which allows the antibody to which it is attached to be detected, and / or further quantified if desired. In some embodiments, the labeling group is coupled to the antibody via spacer arms of various lengths to reduce potential steric hindrance. Various methods for labeling proteins are known in the art and may be used in performing the present invention. Compound activating the peroxisome proliferator-activated gamma receptor (PPARy) may be for example an agonist of peroxisome proliferator-activated gamma receptor (PPARy) selected from the group comprising pioglitazone (N° CAS : 111025-46-8), rosiglitazone (N° CAS : 122320-73-4), glitazones, troglitazone (97322-87-7), ciglitazone (N° CAS : 74772-77-3), farglitazar (N° CAS : 196808-45-4), saroglitazar (N° CAS : 495399-09-2), ATX08-001 (N° CAS : 193012-35-0), Ged-0507-34-Levo (N° CAS : 921195-93-9), T3D-959 (N° CAS : 1258076-66-2), IVA-337 (N° CAS : 927961 -18-0), KDT-501 (N° CAS : 1374259- 84-3), CS-038 (N° CAS : 743438-45-1 , CHS-131 (N° CAS : 315224-26-1 ), S26948 (N° CAS : 353280-43-0), INT131 (N° CAS : 315224-26-1 ), docosahexaenoic acid (N° CAS : 6217-54-5), eicosapentaenoic acid (N° CAS : 10417-94-4), inolitazone dihydrochloride (RS5444) (N° CAS : 223132-37-4), 9- and 13- hydroxyoctadecadienoic acid (N° CAS : 73543-67-6 and 29623-28-7) , 15-deoxy 12,14-prostaglandin J2 (87893-55-8), prostaglandin J2 (PGJ2) (N° CAS 60203-57-8), 15S-Hydroxyeicosatetraenoic acid (15S-HETE) (N° CAS 54845-95-3), preferably 15S-Hydroxyeicosatetraenoic acid (15S-HETE). It may be for example an agonist, for example as disclosed in Takada et al, 2020.

[0058] In the present “cancer involving small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM)” means cancer wherein small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM) are present for example in the microenvironment of a cancer (e.g., tumor) and / or for example, in cancerous tissue (e.g., tumor tissue) and / or for example in peritoneal cavity and / or for example in ascite, for example in tumora site. It may be for example cancer wherein small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM) are present for example in the microenvironment of a cancer (e.g., tumor) and / or for example, in cancerous tissue (e.g., tumor tissue) and / or for example in peritoneal cavity and / or for example in ascite, for example in tumora site in a value of the ratio of SPM / LPM from 7 to 2, from 6 to 2, from 8 to 3, for example from 6,7 to 2. It may be for example cancer wherein small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM) are present in the peritoneal cavity and / or for example in ascite. It may be for example cancer wherein small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM) are present for example in the microenvironment of a cancer (e.g., tumor) or for example, in cancerous tissue (e.g., tumor tissue) and / or for example in peritoneal cavity and / or for example in ascite, and for example, wherein the number of small peritoneal macrophages (SPM) in the microenvironment of a cancer (e.g., tumor) or for example, in cancerous tissue (e.g., tumor tissue) is superior to the number of large peritoneal macrophages (LPM). It may be for example cancer wherein the ratio of (number of small peritoneal macrophages (SPM) I large peritoneal macrophages (LPM)) in the microenvironment of a cancer (e.g., tumor) or for example, in cancerous tissue (e.g., tumor tissue) is superior to 1 , for example about 2, 3, 4. It may be for example cancer comprising peritoneal carcinosis. It may be for example cancer comprising peritoneal carcinosis comprising ascite. It may be for example cancer comprising peritoneal carcinosis selected from the group comprising ovarian cancer, pancreatic cancer, colon cancer, lymphoma, uterus cancer, cervix cancer, colorectal cancer, stomach cancer, pancreas cancer, breast cancer and liver cancer. It may be for example cancer selected from the group comprising ovarian cancer, pancreatic cancer, colon cancer, lymphoma, uterus cancer, cervix cancer, colorectal cancer, stomach cancer, pancreas cancer, breast cancer and liver cancer.

[0059] In the present, the compound of the invention may be used in a combination therapy, for example with a therapeutic agent.

[0060] In the present, the compound of the invention may be used in a combination, for example with a therapeutic agent.

[0061] In the present, the compound of the invention may be used in a combination, for example with anti-cancer drug, anti-angiogenic drug, anti-inflammatory drug, anti-oxidative drug, immunotherapy.

[0062] Combination therapy" (or "co-therapy") includes the administration of a compound activating the peroxisome prol iterator-activated receptors gamma (PPARy). and / or pharmaceutical composition of the invention, and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).

[0063] "Combination therapy" may, but generally is not, intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention. "Combination therapy" is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.

[0064] Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, topical routes, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by injection while the other therapeutic agents of the combination may be administered topically.

[0065] A “therapeutic agent” is any compound known in the art that is used in the detection, diagnosis, or treatment of a condition or disease. Such compounds may be naturally-occurring, modified, or synthetic. Non-limiting examples of therapeutic agents may include drugs, therapeutic compounds, genetic materials, metals (such as radioactive isotopes), proteins, peptides, carbohydrates, lipids, steroids, nucleic acid-based materials, or derivatives, analogues, or combinations thereof in their native form or derivatized with hydrophobic or charged moieties to enhance incorporation or adsorption into a cell. Non-limiting examples of therapeutic agents may include immune-related agents, thyroid agents, respiratory products, antineoplastic agents, anti-helm intics, anti-malarials, mitotic inhibitors, hormones, anti-protozoans, anti-tuberculars, cardiovascular products, blood products, biological response modifiers, anti-fungal agents, vitamins, peptides, anti-allergic agents, anti-coagulation agents, circulatory drugs, metabolic potentiators, anti-virals, anti-anginals, antibiotics, anti-inflammatories, anti-rheumatics, narcotics, cardiac glycosides, neuromuscular blockers, sedatives, local anesthetics, general anesthetics, or radioactive atoms or ions. A therapeutic agent may be a toxin, a small therapeutic molecule, a therapeutic nucleic acid, or a chemotherapeutic agent. A chemotherapeutic agent refers to a chemical compound that is useful in the treatment of cancer. The compound may be a cytotoxic agent that affects rapidly dividing cells in general, or it may be a targeted therapeutic agent that affects the deregulated proteins of cancer cells.

[0066] In the present, the therapeutic agent may be preferably selected from group comprising anticancer drug, anti-inflammatory drug, anti-angiogenic drug, anti- oxidative drug, immunotherapy.

[0067] In the present, the therapeutic agent may be anticancer drug. It may be for example 5 fluoro-uracile (5FU), oxaliplatine. It may be a cytotoxic drug. As used herein, the term “cytotoxic drug” refers to a molecule that when entering in contact with a cell, optionally upon internalization into the cell, alters a cell function (for example cell growth and / or proliferation and / or differentiation and / or metabolism such as protein and / or DNA synthesis) in a detrimental way or leads to cell death. As used herein, the term “cytotoxic drug” encompasses toxins, in particular cytotoxins. It may be, for example, a compound selected from the group comprising calicheamycin, dolastin 10, dolastin 15, auristatin E, auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin F (MMAF), monomethylauristatin-D (MMAD), monomethyl auristatin E (MMAE), and 5- benzoylvaleric acid-AE ester (AEVB) and duocarmycin; nitrogen mustard analogues for example cyclophosphamide, melphalan, ifosfamide or trofosfamide; ethylenimines such as thiotepa; nitrosoureas for example carmustine; alkylating agents for example temozolomide or dacarbazine; folate- like metabolic antagonists such as methotrexate or raltitrexed; purine analogues for example thioguanine, cladribine or fludarabine; pyrimidine analogues for example fluorouracil, tegafur or gemcitabine; vinca alkaloids for example vinblastine, vincristine or vinorelbine and analogues thereof; podophyllotoxin derivatives for example etoposide, taxans, docetaxel or paclitaxel; anthracyclines for example doxorubicin, epirubicin, idarubicin and mitoxantrone, and analogues thereof; other cytotoxic antibiotics for example bleomycin and mitomycin; platinum compounds for example cisplatin, carboplatin and oxaliplatin; pentostatin, miltefosine, estramustine, topotecan, irinotecan and bicalutamide, and toxins for example ricin toxin, liatoxin and Vero toxin.

[0068] In the present, the therapeutic agent may be an anti-angiogenic drug. It may be for example any anti-angiogenic drug known from one skilled in the art. It may be for example an anti-angiogenic drug selected from the group comprising bevacizumab, itraconazole, carboxyamidotriazole, TNP-470, IFN-a, IL-12, suramin, SU5416, thrombospondin, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, tetrathiomolybdate, thalidomide, thrombospondin, prolactin, linomide, ramucirumab, tasquinimod, ranibizumab, sorafenib, sunitinib, pazopanib and everolimus.

[0069] In the present, the therapeutic agent may be an anti-inflammatory drug. It may be for example any an anti-inflammatory drug known from one skilled in the art. It may be for example Nonsteroidal anti-inflammatory drugs, It may be for example anti-inflammatory drug selected from the group comprising aspirin, ibuprofen, naproxen ibuprofen, diclofenac, celecoxib, mefenamic acid, etoricoxib, indomethacin.

[0070] In the present, the therapeutic agent may be an anti-oxydative drug. It may be for example any anti-oxydative drug known from one skilled in the art. It may be for example an anti-oxydative drug selected from the group comprising ascorbic acid, vitamin A, vitamin E, lipoic acid, masoprocol, pramipexole, nitric oxide, allopurinol, pentoxifylline, melatonin, dimethyl sulfoxide, probucol, 3,4- dihydroxycinnamic acid, resveratrol, 3-hydroxyanthranilic acid, dihydrolipoic acid, p-coumaric acid, quercetin, aeol 10150, transcrocetinate, acetylcysteine, nicaraven, lodoxamide, ferulic acid, uric acid, idebenone, chromic chloride, thiosulfuric acid.

[0071] In the present, the therapeutic agent may be an immunotherapy, It may be for example any immunotherapy known from one skilled in the art. It may be for example an immunotherapy selected from the group comprising pembrolizumab, nivolumab, pidilizumab, avelumab. In the present, the administration of the medicament may be carried out by any way known to one skilled in the art. It may, for example, be carried out directly, i.e. pure or substantially pure, or after mixing of a compound activating the peroxisome proliferator-activated receptors gamma (PPARy) with a pharmaceutically acceptable carrier and / or medium. According to the present invention, the medicament may be an injectable solution, a medicament for oral administration, for example selected from the group comprising a liquid formulation, a multiparticle system, an orodispersible dosage form. According to the present invention, the medicament may be a medicament for oral administration selected from the group comprising a liquid formulation, an oral effervescent dosage form, an oral powder, a multiparticle system, an orodispersible dosage form.

[0072] The medicament may be in any form that can be administered to a human or an animal. It may for example be a pharmaceutical composition as defined below.

[0073] Another object of the present invention is a pharmaceutical composition comprising a compound activating the peroxisome proliferator-activated receptors gamma (PPARy) for use in the prevention and / or treatment of cancer involving small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM).

[0074] The pharmaceutical composition may be in any form that can be administered to a human or an animal. The person skilled in the art clearly understands that the term “form” as used herein refers to the pharmaceutical formulation of the medicament for its practical use. For example, the medicament may be in a form selected from the group comprising an injectable form, an oral suspension, a pellet, a powder, granules or topical form.

[0075] The pharmaceutical composition may comprise a pharmaceutically acceptable carrier.

[0076] The pharmaceutically acceptable carrier may be any known pharmaceutical support used for the administration of a drug to a human or animal, depending on the subject to be treated. It may be for example a pharmaceutically acceptable carrier selected from the group comprising, excipients such as sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, and calcium carbonate; binders such as cellulose, methylcellulose, hydroxylpropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, and starch; disintegrants such as starch, carboxymethylcellulose, hydroxylpropylstarch, sodium-glycol-starch, sodium hydrogen carbonate, calcium phosphate, and calcium citrate; lubricants such as magnesium stearate, Aerosil, talc, and sodium lauryl sulfate; flavoring agents such as citric acid, menthol, glycyrrhizin-ammonium salt, glycine, and orange powder; preservatives such as sodium benzoate, sodium hydrogen sulfite, methylparaben, and propylparaben; stabilizers such as citric acid, sodium citrate, and acetic acid; suspending agents such as methylcellulose, polyvinylpyrrolidone, and aluminum stearate; dispersing agents such as surfactants; diluents such as water, physiological saline, and orange juice; base waxes such as cacao butter, polyethylene glycol, and kerosene; and the like.

[0077] According to the invention, the pharmaceutical composition may be administrated by any adapted route of administration known to one skilled in the art. For example, the pharmaceutical composition may be administrated by oral administration and / or parenteral administration.

[0078] The compound activating the peroxisome prol iterator-activated receptors gamma (PPARy) is as defined above.

[0079] In the present, the composition may comprise therapeutical effective concentration of compound activating the peroxisome proliferator-activated receptors gamma (PPARy). It may be any therapeutical effective concentration of compound activating the peroxisome proliferator-activated receptors gamma (PPARy) known from one skilled in the art.

[0080] For example, in the case of cancer, the therapeutically effective amount of compound activating the peroxisome proliferator-activated receptors gamma (PPARy) may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e. slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e. slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve to some extent one or more of the symptoms associated with the cancer. For example in the case of cancer, the therapeutically effective amount of compound activating the peroxisome proliferator-activated receptors gamma (PPARy) may change in the peritoneal macrophage balance by increasing the differentiation from immunosuppressive SPM to LPM and / or a promotion of LPM peritoneal residence and / or increasing the effector / regulatory T cell ratio.

[0081] The administration of the compound activating the peroxisome proliferator- activated receptors gamma (PPARy) or pharmaceutical composition comprising the compound activating the peroxisome proliferator-activated receptors gamma (PPARy) may be performed topically, orally, respiratory or by injection

[0082] The compound activating the peroxisome proliferator-activated receptors gamma (PPARy) or composition comprising a compound activating the peroxisome proliferator-activated receptors gamma (PPARy) may be, for example, administered daily, twice daily and weekly or less. It may be, for example, administered once a day, twice a day or less, for example once every other day, or weekly.

[0083] According to the invention, the compound activating the peroxisome proliferator-activated receptors gamma (PPARy) or composition comprising a compound activating the peroxisome proliferator-activated receptors gamma (PPARy) may be, for example, administered over a period of 1 day to 3 months, for example for 2 months. For example, the compound activating the peroxisome proliferator-activated receptors gamma (PPARy) or composition comprising the compound activating the peroxisome proliferator-activated receptors gamma (PPARy) may be administered over a period of 3 or 6 months, for example with a frequency of administration every day.

[0084] For example, when the composition is in an injectable form, the composition may be administered with a frequency of administration every 3 or 6 months or less.

[0085] The present invention also relates to a method of treating a patient having cancer involving small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM) a comprising administering at least one compound activating the peroxisome proliferator-activated receptors gamma (PPARy) or composition comprising a compound activating the peroxisome proliferator- activated receptors gamma (PPARy). The compound activating the peroxisome prol iterator-activated receptors gamma (PPARy) is as defined above.

[0086] The composition comprising a compound activating the peroxisome prol iterator-activated receptors gamma (PPARy) is as defined above.

[0087] The cancer involving small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM) is as defined above.

[0088] According to the invention, the patient may be any mammal. For example, it may be an animal or a human being.

[0089] According to the invention, the mode and / or route of administration of a compound activating the peroxisome prol iterator-activated receptors gamma (PPARy) or the composition comprising a compound activating the peroxisome prol iterator-activated receptors gamma (PPARy) may be as defined above.

[0090] According to the invention, the mode and / or route of administration of may be as defined above, preferably topical, intravenous, intraperitoneal, per os.

[0091] According to the invention the frequency of administration of the compound activating the peroxisome prol iterator-activated receptors gamma (PPARy) or the composition comprising a compound activating the peroxisome proliferator- activated receptors gamma (PPARy) may be as defined above.

[0092] Other advantages may still be apparent to those skilled in the art by reading the examples below, illustrated by the accompanying figures, given by way of illustration.

[0093] Brief description of the figures:

[0094] Figure 1: Figure 1 A represents pictures of tumor burden in peritoneal membrane, diaphragm and ascites of untreated with 15(S)-HETE every four days ID8 tumor-bearing mice (8-9 weeks old C57BL / 6 female mice were injected intraperitoneally with 5 x 106ID8-Luc cells) 50 days’ post-injection. Figure 1 B represents In vivo imaging of luciferase activity in the abdomen of8-9 weeks old C57BL / 6 female mice 7, 18, 35 or 50 days after intraperitoneally injection of 5 x 106ID8-Luc cells treated or not with 15(S)-HETE every four days. Figure 1 C is a histogram representing the luciferase activity (ordinate), quantified by bioluminescence, measured at the peritoneal membrane of 8-9 weeks old C57BL / 6 female mice 7, 18 or 35 days after intraperitoneally injection of 5 x 106 ID8-Luc cells treated (grey bar) or not (black bar) with 15(S)-HETE every four days. Figure 1 D is a histogram representing the luciferase activity (ordinate), quantified by bioluminescence, measured at the diaphragm of 8-9 week old C57BL / 6 female mice 7, 18 or 35 days after intraperitoneally injection of 5 x 106ID8-Luc cells treated (grey bar) or not (black bar) with 15(S)-HETE every four days. Figure 1 E is a histogram representing the luciferase activity (ordinate), quantified by bioluminescence, measured at the ascites of 8-9 weeks old C57BL / 6 female mice 7, 18 or 35 days after intraperitoneally injection of 5 x 106ID8-Luc cells treated (grey bar) or not (black bar) with 15(S)-HETE every four days. Figure 1 F represents a histogram of ascites volume in mL (ordinate) and weight gain in gram (g) of untreated (black bar) and 15(S)-HETE-treated mice (grey bar) 50 days’ post tumor cells (ID8-Luc cells) injection. Figure 1 G represents a histogram of cytotoxic activity of peritoneal macrophages collected from the tumor ascites of untreated (black bar) and 15(S)-HETE-treated (grey bar) mice measured by the percentage of ID8 cell death (ordinate) determined by the quantification of bioluminescence intensity after 72h of co-culture with ID8- Luc tumor cells. Figure 1 H represent histograms measuring the relative luciferase activity (ordinate) at the peritoneal membrane of 8-9 weeks old C57BL / 6 female mice treated (+) or not (-) intraperitoneally with clodronate 1 day before injection of 5 x 106ID8-Luc cells, and then every 4 days, said mice being also treated (grey bar) or not (black bar) with 15(S)-HETE. Figure 1 I represent histograms measuring the relative weight gain of ascites (A VALIFER) of 8-9 weeks old C57BL / 6 female mice treated (+) or not (-) intraperitoneally with clodronate 1 day before injection of 5 x 106ID8-Luc cells, and then every 4 days, said mice being also treated (grey bar) or not (black bar) with 15(S)-HETE. Weight gain is expressed as fold induction relative to corresponding untreated ID8 tumor-bearing mice. Results correspond to mean ± SEM (n=6 per group) and are representative of at least three independent experiments. * p < 0.05, ** p < 0.01 , *** p < 0.001 and **** p < 0.0001 compared to respective untreated ID8 tumor-bearing mice. # p< 0.05 and ## p < 0.01 compared to untreated mice at day 7.

[0095] Figure 2: Figure 2A represents a Dot-Plot showing Small Peritoneal Macrophages (SPM, F4 / 80|OWMHCIIhigh) and Large Peritoneal Macrophages (LPM, F4 / 80highMHCII|OW) day 18 post injection of 8-9 weeks old C57BL / 6 female mice injected, or not (control mice), intraperitoneally with 5 x 106ID8-Luc2 cells and treated or not with 15(S)-HETE every four days. Figure 1 B represents histogram quantification in percentage of SPM (F4 / 80|OWMHCIIhigh) and LPM (F4 / 80highM HC I llow) in F4 / 80+ MHCII+ population at days 7, 18 and 35 post-tumor cell injection ), intraperitoneally with 5 x 106ID8-Luc2 cells of 8-9 weeks old C57BL / 6 female mice injected and treated (grey bar) or not (black bar) with 15(S)- HETE every four days. Figure 1 C represents histograms of mRNA expression (ordinate) of SPM and LPM differentiation markers, SPM and LPM coming from the ascites of untreated or 15(S)-HETE-treated (grey bar) or not (black bar) mice were sorted at day 18 post-ID8 injection using F4 / 80 and MHCII markers. Figure 1 D represents a histogram of the percentage of CD45.1+macrophage subpopulation (ordinate) from CD45.1+flushed bone marrow cells injected in intra-orbital to CD45.2+host tumor-bearing mice treated (grey bar) or not (black bar) with 15(S)-HETE at day 11 post tumor cells injection. SPM-to-LPM differentiation was quantified by flow cytometry using F4 / 80, MCHII, CD45.1 and CD45.2 markers. Figure 1 E is a histogram representing the percentage of CD45.1+F4 / 80+cells (ordinate) from CD45.1+flushed bone marrow cells injected in intra-orbital to CD45.2+host tumor-bearing mice treated (grey bar) or not (black bar) with 15(S)-HETE at day 11 post tumor cells injection. Figure 2 F represents histograms of mRNA relative expression (ordinate) of SPM to LPM differentiation markers, SPM and LPM coming from the ascites of untreated or 15(S)-HETE- treated (grey bar) or not (black bar) mice were sorted at day 18 post-ID8 injection using F4 / 80 and MHCII markers. Figure 2 G represents a histogram of the percentage of BrDU+ macrophage subpopulation (ordinate) from mice in which 3 hours before euthanasia, tumor bearing mice treated (grey bar) or not (black bar) with 15(S)-HETE were injected with BrdU. BrdU incorporation was assessed by flow cytometry. Figure 2 H represents histograms of mRNA expression of peritoneal residency markers genes in SPM and LPM, i.e Gata6, Serpinb2, Selp and Thbsl using RT-qPCR from 8-9 weeks old C57BL / 6 female mice injected intraperitoneally with 5 x 106ID8-Luc2 cells and treated (grey bar) or not (black bar) with 15(S)-HETE and sorted at day 18 post-ID8 injection. (I) Quantification of LPM in the peritoneum and omentum at day 18 post-tumor cell injection. Results correspond to mean ± SEM (n=6 per group) and are representative of at least three independent experiments. * p < 0.05, ** p < 0.01 , *** p < 0.001 and **** p < 0.0001 compared to respective untreated ID8 tumor-bearing mice. ## p < 0.01 and #### p < 0.0001 compared to SPM from untreated ID8 tumor-bearing mice.

[0096] Figure 3: Figure 3 A represents a histogram of percentage of F4 / 80+ cells (ordinate) from flow cytometry of PPARy, C / EBP[3 and GATA6 staining on SPM and LPM population from 8-9 weeks old C57BL / 6 female mice injected intraperitoneally with 5 x 106ID8-Luc cells and treated (grey bar) or not (black bar) with 15(S)-HETE every four days. Figure 3 B represents imaging flow cytometry channels of macrophages, SPM and LPM population, in peritoneal fluid stained with DAPI, F4 / 80, MHCII, PPARy, C / EBP[3, merge DAPI-PPARy, merge DAPI-C / EBP[3 and merge DAPI-C / EBP[3 from 8-9 weeks old C57BL / 6 female mice injected intraperitoneally with 5 x 106ID8-Luc cells and treated or not with 15(S)-HETE every four days. Figure 3C represents imaging flow cytometry channels of macrophages, SPM and LPM population, in peritoneal fluid stained with DAPI, F4 / 80, MHCII, PPARy, GATA6, merge DAPI- GATA6, merge PPARy- GATA6 from 8-9 weeks old C57BL / 6 female mice injected intraperitoneally with 5 x 106ID8-Luc cells and treated or not with 15(S)-HETE every four days. Figure 3D represent diagrams of quantification of PPARy, C / EBP[3 and GATA-6 on SPM and LPM from untreated or treated tumor-bearing mice by Image StreamX.. Figure 3E represents histogram of mRNA expression of SPM-to-LPM differentiation markers, i.e C / EBP[3 and GATA6 using RT-qPCR from 8-9 week old female wild-type mice (PPARyM+ / +) or in mice in which the PPARy gene was selectively disrupted in myeloid-derived cells (PPARYM' / _) in which 5 x 106ID8- Luc cells were injected intraperitoneally, the mice being treated (grey bar) or not (black bar) with 15(S)-HETE every four days, SPM and LPM being obtained day 18 post- ID8-Luc cells injection using F4 / 80 and MHCII markers from the ascites. Figure 3F represents histogram of mRNA expression of peritoneal residency marker, i.e. Gata6, Serpinb2 and Selp using RT-qPCR from 8-9 week old female wild-type mice (PPARyM+ / +) or in mice in which the PPARy gene was selectively disrupted in myeloid-derived cells (PPARYM' / _) in which 5 x 106ID8-Luc cells were injected intraperitoneally, the mice being treated (grey bar) or not (black bar) with 15(S)-HETE every four days, SPM and LPM being obtained day 18 post- ID8-Luc cells injection using F4 / 80 and MHCII markers from the ascites. Results correspond to mean ± SEM (n=6 per group) and are representative of at least three independent experiments. * p < 0.05, ** p < 0.01 and *** p < 0.001 compared to respective untreated ID8 tumor-bearing mice.

[0097] Figure 4 : Figure 4A represents histogram of mRNA expression of chemotaxis, immunosuppression, angiogenesis, metastasis factors and of pro or antiinflammatory cytokines using RT-qPCR of SPM and LPM from 8-9 weeks old C57BL / 6 female mice in which were injected intraperitoneally with 5 x 106ID8- Luc cells and were then treated (grey bar) or not (black bar) with 15(S)-HETE every four days, SPM and LPM were sorted at day 18 post-ID8 injection using F4 / 80 and MHCII markers. Figure 4B represents histogram of protein expression (concentration in pg / mL) of chemotactic factors and pro- or anti-inflammatory cytokines in tumor ascites was evaluated by flow cytometry from 8-9 weeks old C57BL / 6 female mice in which were injected intraperitoneally with 5 x 106ID8- Luc cells and were then treated (grey bar) or not (black bar) with 15(S)-HETE every four days, the protein expression being measured at day 18 or 35 post I D8- Luc cells injection. Results correspond to mean ± SEM (n=6 per group) and are representative of at least three independent experiments. * p < 0.05, ** p < 0.01 and *** p < 0.001 compared to respective untreated ID8 tumor-bearing mice. # p < 0.05, ## p < 0.01 , ### p < 0.001 and #### p < 0.0001 compared to SPM from untreated ID8 tumor-bearing mice.

[0098] Figure 5: Figure 5 A represents cell number (ordinate) from 8-9 week old C57BL / 6 female mice injected intraperitoneally with 5 x 106ID8-Luc cells and treated (grey bar) or not (black bar) with 15(S)-HETE every four days, in particular macrophage and lymphocyte in the peritoneum at days 7 (d7), 18 (d18) and 35 (d35) post cell injection evaluated by flow cytometry after staining with appropriated markers (NK1.1 , F4 / 80, CD3, CD4, CD25, CD8, CD25, FoxP3 and CD19). Figure 5B : represents a Dot-Plot showing Th1 / Th2 CD4+ lymphocytes from 8-9 week old C57BL / 6 female mice injected intraperitoneally with 5 x 106ID8-Luc cells and treated or not with 15(S)-HETE every four days, at day 35 post- 108 injection, evaluated by flow cytometry after staining with CD183 antibody (Miltenyi Biotec) and a histogram of the percentage of Th1 / Th2 CD4+ lymphocytes in CD4+ population (ordinate) at day 35 post-ID8 injection, mice being treated (grey bar) or not (black bar) with 15(S)-HETE every four days. Figure 5C represents a Dot-Plot showing cytotoxic CD8+ lymphocytes after staining with CD183 antibody, from 8-9 week old C57BL / 6 female mice injected intraperitoneally with 5 x 106ID8-Luc cells and treated or not with 15(S)-HETE every four days, at day 35 post-ID8 injection, evaluated by flow cytometry and an histogram of the percentage of cytotoxic CD8+ lymphocytes (CD3+, CD8+CD183+) in CD8+ population at day 35 post-ID8 injection, mice being treated (grey bar) or not (black bar) with 15(S)-HETE every four days. Figure 4 D represents a histogram of mRNA expression (ordinate) of lymphocytes activation at day 35 post-ID8 injection, evaluated by analyzing Prf1 (perforin), Gzmb (Granzyme B) and Faslg (Fas ligand) expression using RT-qPCR, mice being treated (grey bar) or not (black bar) with 15(S)-HETE every four days. Figure 5E represents histograms of relative luciferase activity representing tumor burden evaluated at day 35 post-tumor cell injection from wild-type (RAG-2+ / +) or RAG-2 deficient mice (RAG-2’ / _) injected intraperitoneally with 5 x 106ID8-Luc2 cells treated (grey bar) or not with 15(S)-HETE (black bar) every four days in peritoneal membrane, diaphragm and ascites. Tumor burden data are expressed as fold induction relative to the corresponding untreated ID8 tumor-bearing mice. Figure 5F represents histogram of relative cell number CD4+CD25+FoxP3+ (Tregs) infiltrated in ascites from 8-9 weeks old C57BL / 6 female mice treated intraperitoneally with clodronate (+) or not (-) 1 day before injection intraperitoneally of 5 x 106ID8-Luc cells and then every 4 days and treated (grey bar) or not (black bar) with 15(S)-HETE every four days. Figure 5G represents histogram of Th1 CD4+ CD183 cells (lymphocytes) number Th1 CD4+ CD183 cells (lymphocytes) infiltrated in ascites from 8-9 weeks old C57BL / 6 female mice treated intraperitoneally with clodronate (+) or not (-) 1 day before injection intraperitoneally of 5 x 106ID8-Luc cells and then every 4 days and treated (grey bar) or not (black bar) with 15(S)-HETE every four days. Figure 5H represents histogram of cytotoxic CD8+ lymphocytes cell number infiltrated in ascites from 8-9 weeks old C57BL / 6 female mice treated intraperitoneally with clodronate (+) or not (-) 1 day before injection intraperitoneally of 5 x 106ID8-Luc cells and then every 4 days and treated (grey bar) or not (black bar) with 15(S)-HETE every four days. Data are expressed as fold induction relative to the corresponding untreated ID8 tumor-bearing mice. Results correspond to mean ± SEM (n=6 per group) and are representative of at least three independent experiments. * p < 0.05, ** p < 0.01 and *** p < 0.001 compared to respective untreated ID8 tumorbearing mice. # p < 0.05, ## p < 0.01 and ### p < 0.001 compared to untreated mice at day 7.

[0099] Figure 6: Figure 6A represents ascites and diaphragm tumor burden quantified by bioluminescence, i.e. luciferase activity, at day 35 post-tumor cell injection of 5 x 106ID8-Luc cells intraperitoneally in 8-9 weeks old female wild-type mice (PPARyM+ / +) or in mice in which the PPARy gene was selectively disrupted in myeloid-derived cells (PPARy1^-7’). Mice were then treated (grey bar) or not (black bar) with 15(S)-HETE every four days. Figure 6 B represents Dot-Plot and histogram quantification of SPM and LPM in F4 / 80+ MHCII+ population at day 35 post-tumor cell injection, with 5 x 106ID8-Luc cells intraperitoneally in 8-9 week old female wild-type mice (PPARyM+ / +) or in mice in which the PPARy gene was selectively disrupted in myeloid-derived cells (PPARyM’ / _), mice being treated (grey bar) or not (black bar) with 15(S)-HETE every four days, after F4 / 80 and MHCII staining. Figure 6C represents histogram representing the CD3+CD4+CD8+, CD3+CD8+ or CD4+CD25+FoxP3+ cell number infiltrated in ascites at day 35 post-tumor cell injection, with 5 x 106ID8-Luc cells intraperitoneally in 8-9 weeks old female wild-type mice (PPARyM+ / +) or in mice in which the PPARy gene was selectively disrupted in myeloid-derived cells mice being treated (grey bar) or not (black bar) with 15(S)-HETE every four days evaluated by flow cytometry. Figure 6D represents the percentage of Th1 CD4+ lymphocytes in CD4+ population at day 35 post-tumor cell injection, with 5 x 106ID8-Luc cells intraperitoneally in 8-9 weeks old female wild-type mice (PPARyM+ / +) or in mice in which the PPARy gene was selectively disrupted in myeloid-derived cells (PPARyM’ / _), mice being treated (grey bar) or not (black bar) with 15(S)-HETE every four days. Figure 6E represents the percentage of cytotoxic CD8+CD183+ lymphocytes in CD8+ population evaluated by flow cytometry with appropriate markers at day 35 post-tumor cell injection, with 5 x 106ID8-Luc cells intraperitoneally in 8-9 weeks old female wild- type mice (PPARyM+ / +) or in mice in which the PPARy gene was selectively disrupted in myeloid-derived cells (PPARYM- / _), mice being treated (grey bar) or not (black bar) with 15(S)-HETE every four days. Results correspond to mean ± SEM (n=6 per group) and are representative of at least three independent experiments. * p < 0.05, ** p < 0.01 and *** p < 0.001 compared to respective untreated ID8 tumor-bearing mice. # p < 0.05 and ## p < 0.01 compared to PPARyMs+ / +untreated mice.

[0100] Figure 7: Figure 7A represents dot-plot showing infiltrated macrophages (CD14interCD16|OW) and Resident macrophages (CD14highCD16high) characterized by flow cytometry from ovarian cancer patients’ tumor ascites. Figure 7B represents histogram quantification (percentage of CD14+CD16+ / - cells (ordinate) of Infiltrated, Intermediate and Resident macrophages in CD14+ CD16+ / - population (n=31 patients), showing infiltrated macrophages (CD14interCD16|OW) and Resident macrophages (CD14highCD16high) characterized from ovarian cancer patients’ tumor ascites. Figure 7C represents histogram of mRNA expression of SPM and LPM differentiation markers, i.e. ITGAM, 15LOX2, HLADR, CLEC7A of macrophages were then treated (+) or not (-) with 15(S)- HETE (1 pM) during 48h. Figure 7D represents histogram of mRNA expression factors involved in SPM-to-LPM differentiation, C / EBP6, CYP27B1 , LGALS3, PTKB2. and LPM residency i.e. GATA6, SELP, SERPINB2, THBS1 of macrophages. Figure 7E represents histogram of mRNA expression of immunosuppression and metastasis factors. Results are expressed as fold induction relative to untreated TAM and correspond to mean ± SEM of TAMs isolated from 16 patients. * p < 0.05 and ** p < 0.01 compared to the respective untreated tumor-associated macrophages.

[0101] Figure 8 is a schematic illustration of the 15(S)-HETE treatment on ovarian peritoneal carcinomatosis. 15(S)-HETE: 15(S)-Hydroxyeicosatetraenoic acid; C / EBPp: CCAAT / Enhancer Binding Protein P; CCL-: C-C motif chemokine Ligand-; LPM: Large Peritoneal Macrophage; MMP9: Matrix Metalloproteinase; PDL-: Programmed Death-Ligand-; PPARy: Peroxisome Proliferator-Activated Receptor y; SPM: Small Peritoneal Macrophage; Treg: Regulatory T cell and VEGFa: Vascular Endothelial Growth Factor-a. Figure 9: Figure 9A represents an histogram of the percentage of peritoneal immune living cells (CD45+ immune cells proportion in living peritoneal cells) (ordinate) from 8-9 weeks old C57BL / 6 female mice treated intraperitoneally with clodronate 1 day before intraperitoneally injection of 5 x 106ID8-Luc cells then every 4 days, mice being treated (grey bar) or not (black bar) with 15(S)-HETE every four days and. Peritoneal immune cells were quantified flow cytometry at day 35 post-ID8 implantation. Figure 9B represents an histogram of the percentage of peritoneal immune living cells (CD11 b+ myeloid cells proportion in living peritoneal cells) (ordinate) from 8-9 week old C57BL / 6 female mice treated intraperitoneally with clodronate 1 day before intraperitoneally injection of 5 x 106ID8-Luc cells then every 4 days, mice being treated (grey bar) or not (black bar) with 15(S)-HETE every four days and. Peritoneal immune cells were quantified flow cytometry at day 35 post-ID8 implantation. Figure 9C represents a histogram of the percentage of peritoneal immune living cells (F4 / 80+ macrophages proportion in living peritoneal cells) (ordinate) from 8-9 weeks old C57BL / 6 female mice treated intraperitoneally with clodronate 1 day before intraperitoneally injection of 5 x 106ID8-Luc cells then every 4 days, mice being treated (grey bar) or not (black bar) with 15(S)-HETE every four days and. Peritoneal immune cells were quantified flow cytometry at day 35 post-ID8 implantation. Results correspond to mean ± SEM (n=6 per group) and are representative of at least three independent experiments. * p < 0.05 compared to respective clodronate untreated ID8 tumor-bearing mice.

[0102] Figure 10 represents pictures of flow cytometry of macrophages from 8-9 weeks old C57BL / 6 female mice with 5 x 106ID8-Luc cells injected intraperitoneally and treated or not with 15(S)-HETE every four days. The macrophages being stained with F4 / 80 and MHCII in peritoneal fluid collected from untreated or 15(S)-HETE- treated tumor-bearing mice. Cell nuclei being stained with DAPI, and PPARy, C / EBP[3 or GATA6 expression were analyzed. Different merges were performed to represent nuclear translocation (transcription factors and nucleus staining) and co-localization of PPARy with C / EBP[3 or GATA6.

[0103] Figure 11 : Figure 11 A represents histogram of luciferase activity in ascites from 8-9 weeks old C57BL / 6 female mice were injected intraperitoneally with 5 x 106ID8-Luc cells treated (mid-grey bar) or not (black bar) with 15(S)-HETE or Rosiglitazone (light grey bar) (2,8pg / kg) every four days. Figure 11 B represents histogram of quantification of peritoneal macrophage populations (F4 / 80+ MHCII+) in ascites from 8-9 weeks old C57BL / 6 female mice were injected intraperitoneally with 5 x 106ID8-Luc cells treated (mid-grey bar) or not (black bar) with 15(S)-HETE or Rosiglitazone (light grey bar) (2,8pg / kg) every four days, characterized by flow cytometry at day 18 post-tumor cell (ID8-Luc cells) injection. Figure 11 C represents histogram of mRNA expression of SPM-to-LPM differentiation markers and peritoneal residency markers of peritoneal macrophages coming from the ascites of 8-9 week old C57BL / 6 female mice injected intraperitoneally with 5 x 106ID8-Luc cells, collected at day 18 post-ID8 cells injection and isolated from other peritoneal cells by 2h of adhesion treated (mid-grey bar) or not (black bar) at day 18 post-ID8 cells injection, macrophages were treated by 15(S)-HETE (1 pM), by Rosiglitazone (5pM) during 24h. Results correspond to mean ± SEM (n=6 per group) and are representative of at least three independent experiments. * p < 0.05, ** p < 0.01 , *** p < 0.001 and **** p < 0.0001 compared to respective untreated ID8 tumor-bearing mice. # p < 0.05 and ## p < 0.01 compared to 15(S)-HETE-treated mice.

[0104] Figure 12: Figure 12 presents the gating strategy for ascites tumor-associated macrophages.

[0105] Figure 13: Figure 13 presents the gating strategy for ascites tumor-associated lymphocytes. Figure 13 A represent the Flow gating strategy for lymphocytes, figure 13 B the flow gating strategy for activated CD4 / CD8 T Lymphocytes and figure 13 C the flow gating strategy for T reg Lymphocyte.

[0106] EXAMPLES

[0107] Example 1 : Use of compound activating the peroxisome proliferator- activated gamma receptor (PPARY) for preventing and / or treating cancer involving small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM)

[0108] EXPERIMENTAL PROCEDURES

[0109] Cell culture The murine ovarian cancer cell line ID8 [Ryu et al, 2018] was cultured in Dulbecco's modified Eagle's medium (DMEM, Invitrogen), supplemented with L- glutamine (Invitrogen), penicillin, streptomycin (Invitrogen) and 10% heat- inactivated fetal calf serum (FCS). For bioluminescence quantification, ID8 were transfected with a lentiviral vector encoding firefly luciferase under the control of the CMV promoter as well as a puromycin selection gene (addgene) as previously described [Couderc et al, 2008],

[0110] Mice

[0111] All mouse experiments were performed according to protocols approved by the institutional ethics committee (CEEA122) with permit number 6555- 2016082912056664 v3 in accordance with European legal and institutional guidelines (2010 / 63 / UE) for the care and use of laboratory animals. Wild-type (CD45.1 and CD45.2) C57BL / 6 mice were purchased from JanvierLabs. PPARYM’ / _mice have been described earlier and the corresponding floxed littermates were used as controls throughout all the experiments [Gales et al, 2010 ; Lefevre et al, 2013] RAG-2 / _mice were purchased from Envigo.

[0112] Murine ovarian cancer model, 15(S)-HETE treatment and adoptive transfer

[0113] ID8 cells expressing the luciferase (5.106cells / mouse in 200 pL PBS) were administered intra-peritoneally (i.p.) in 8-9-week-old old syngeneic C57BL / 6 female mice (n=6 per group). This ID8 orthotopic mouse model is a well- established experimental model of end-stage epithelial ovarian carcinoma [Van Vloten 2022],

[0114] Mice were injected i.p. with 15(S)-HETE (Cayman Chemicals) (12pg / mouse, 1 day after ID8 injection and then every 4 days), with Rosiglitazone (Cayman Chemicals) (56pg / mouse, 1 day after ID8 injection and then every 4 days) or, for control groups, with saline solution (NaCI 0.9%). For depleting macrophages, mice were i.p. injected liposomal clodronate experiments (Xygieia Bioscience, 250pg per mouse), 1 day before tumor cell injection (cancer cell line ID8) and then every 4 days; control groups received control Liposome. At 7, 18, 35 or 50 days after ID8 cell injection, mice were euthanized using CO2 asphyxia. Bone marrow cells were collected from CD45.1 C57BL / 6 mice paw bones, femurs and tibias in Phosphate Buffer Salin (PBS) (SIGMA-ALDRICH, Product Number: P5119) and filtered. Red blood cells were lysed and bone marrow monocytes were sorted by negative selection on MACS columns (Monocyte Isolation Kit (BM) mouse, Miltenyi Biotec (ACK Lysing Buffer, Gibco™ catalog number: A1049201 ).

[0115] Bone marrow monocytes were injected in the retro-orbital vein of CD45.2 mice (5.105cells / mouse) 11 days after ID8 cells injection, and mice were i.p treated with 200pL of Bromodeoxyuridine (BrdU) (SIGMA-ALDRICH, Product Number: B5002 ; CAS Number : 59-14-3) (10mg / mL) 3h before being euthanized using CO2 asphyxia 18 days after ID8 injection.

[0116] Assessment of tumor progression

[0117] Mice were monitored daily for signs of tumor progression and evaluation of body weight. For in vivo imaging study, mice were anesthetized by isoflurane i.p. injected with luciferin (150pg / g body weight) and imaged, 6 minutes later with 30 seconds exposure length, using in vivo imaging system (MS, PerkinElmer (https: / / www.perkinelmer.com / fr / category / optical-irnaging)). The luminescent images were analyzed using Living lmage®4.4 software.

[0118] After mice euthanasia, peritoneal cells were removed aseptically and supernatants (ascites fluids) were collected for cytokines measurement. Luciferase activity was measured on peritoneal cell samples and on diaphragm and peritoneal membrane with a luminometer (Envision, PerkinElmer). The volume of ascites fluid was determined by aspirating with a needle and syringe.

[0119] Macrophages cytotoxicity assay

[0120] Macrophages in ascites of mice were separated from other peritoneal cells by a Percoll density gradient (Percoll®, Sigma-Aldrich) followed by 2h of adhesion. Macrophages were co-cultured 72h with ID8 cells then the number of viable ID8 cells was evaluated by measuring the luciferase activity 10 min after D-Luciferin addition (Caliper, 9pg / ml) with a luminometer.

[0121] Flow cytometry After mice euthanasia, peritoneal cells were harvested, centrifuged and red blood cells were lysed with ACK lysing buffer (ACK Lysing Buffer, Gibco™ catalog number: A1049201 ). All analyses were gated on viable cells after a Live / Dead Staining (Molecular Probes® LIVE / DEAD Fixable Violet Dead Cell Stain Kit, Life technologies™).

[0122] For lymphocyte population infiltration / activation and for Th1 / Th2 profile studies, peritoneal cells were labeled with the following antibodies: CD3-PE, CD4-VioBrightFITC, CD8-VioGreen, CD25-PEVio770, NK1 ,1 -PerCPVio700, CD19-APCVio700, CD183-APC and Foxp3-Vio667 (Miltenyi Biotec).

[0123] Peritoneal macrophage population analysis was analyzed by surface expressed MHCII and F4 / 80 detection respectively using MHCII-Vioblue and F4 / 80-APC (Miltenyi Biotec) in CD45+(VioGreen, Miltenyi Biotec) and CD11 b+(FITC, Miltenyi Biotec) cells. To identify the origin of the different populations, CD45.2-PerCPVio770 and CD45.1-PE antibodies (Miltenyi Biotec) were used. Finally, cells were washed and resuspended in 300pL PBS / _1 % heat-inactivated fetal calf serum (FCS). To analyze cells proliferation, peritoneal macrophage populations were stained with anti-BrdU antibody (PE, Miltenyi Biotec).

[0124] Human ascitic macrophage populations were analyzed by surface expressed markers, CD14 and CD16 respectively using CD14-PerCPVio700 (Miltenyi Biotec) and CD16-VioBright R720 (Miltenyi Biotec) antibodies, respectively.

[0125] Appropriate fluorochrome-matched isotype antibodies were used to determine nonspecific background staining. All stainings were performed on 100 pL of PBS / _1 % heat-inactivated fetal calf serum. A population of 10.000 cells was analyzed for each data point. All analyses were done in a BD Fortessa flow cytometer with Diva software. A multiplex bead-based immunoassay was used (BioLegend, LEGENDPlex™ Mix and Match System) for ascites cytokine titration.

[0126] The gating strategies were detailed in Figures 12 and 13. The FSC-A vs SSC-A gating is used to identify distinct cell types in biological sample, for example to identify distinct cell types in red cell lysed whole blood. A Forwardscatter width (FSC-W) vs. forward scatter Area (FSC-A) density plot is used to exclude doublets. The Live dead Violet-Area is used to determine the cells viability and select living cells. The peritoneal cells were stained with the markers CD45, F4 / 80, MHCII and CD3.

[0127] Image Flow Cytometry

[0128] After mice euthanasia, peritoneal cells were harvested, centrifuged and red blood cells were lysed with ACK lysing buffer. Peritoneal macrophage population was analyzed by surface expressed MHCII and F4 / 80 detection, respectively, using MHCII-PE (Miltenyi Biotec) and F4 / 80-PECy7 (eBiosciences) antibodies. Cells were washed, permeabilized then incubated with DAPI for nucleus staining, anti-PPARy antibody (AF680, Bioss) and anti-C / EBPp (FITC, Biorbyt) or anti- GATA6 (FITC, Biorbyt) antibodies. Then, cells were washed and resuspended in 300pL PBS / _1 % heat-inactivated fetal calf serum. Appropriate fluorochrome- matched isotype antibodies were used to determine nonspecific background staining. All stainings were performed on 100 pL of PBS / _1 % heat-inactivated fetal calf serum. Individual cell images were acquired using IDEAS software (Amnis Merck Millipore, Billerica, MA, USA) on a 3-laser 6-channel imaging flow cytometer (Image Stream X Mark II, Amnis Merck Millipore) with *40 magnification. For each data file, at least 50,000 single cells were acquired debris and doublets were excluded based on their area and aspect ratio. Single-stain controls were acquired (all channels on, no brightfield and no side scatter image), a compensation matrix was calculated and then applied to the data files using IDEAS software (Amnis Merck Millipore). Briefly, focus cells were identified using the gradient RMS feature of the brightfield channel (Ch04). Single cells were then identified from debris and cell clusters using a plot of aspect ratio vs. area of the brightfield channel.

[0129] Peritoneal macrophage and lymphocyte cell sorting

[0130] Peritoneal cells were stained with the following markers: CD45-APCy7 (BioLegend), F4 / 80-APC, MHCII-Vioblue and CD3-PE (Miltenyi Biotec). The two peritoneal macrophage populations (Small Peritoneal Macrophages and Large Peritoneal Macrophages) and lymphocytes were sorted with a BD Influx™ cell sorter. Macrophage ex-vivo treatment

[0131] After mice euthanasia, peritoneal cells were harvested, centrifuged and red blood cells were lysed with ACK lysing buffer. Then cells were allowed to adhere during 2h. After washing, tumor-bearing m ice-isolated macrophages were treated or not with 15(S)-HETE (Cayman Chemicals, 1 pM) or Rosiglitazone (Cayman Chemicals, 5pM) during 48h then lysed and used for Real-Time PCR.

[0132] Isolation and treatment of macrophages isolated from patients’ ascites

[0133] Ascitic fluids from individuals with ovarian cancer were collected from chemotherapy-naive patients who underwent a tumor surgical resection. Ascitic fluids were obtained aseptically in heparinized vacuum bottles from patients with pathologically confirmed OVAD. Appropriate informed consents were obtained from all cases. Fluids were passed through a 100 pM filter to obtain a single cell suspension. Tumor-associated macrophages (TAMs) were isolated from patients’ ascites with a Percoll density gradient as described previously [Van Vloten, 2022]

[0134] The fraction containing macrophages was allowed to adhere for 2h and then treated or not with 15(S)-HETE (Cayman Chemicals, 1 pM) for 48h and then lysed and used for Real-Time PCR.

[0135] Reverse Transcription and Real-Time PCR mRNA were isolated using the RNAqueous®-Micro Total RNA Isolation Kit (Thermofisher) following the manufacturer’s protocol and cDNA was synthesized according to the manufacturer’s recommendations (Verso Kit, Thermo electron). RT-qPCR was performed in a total volume of ten microliters with 60 cycles of 10 s at 95°C, 10 s at 60°C and 10 s at 72°C using a LightCycler 480 system using LightCycler SYBR Green I Master (Roche Diagnostics). The primers (at a final concentration of 5 pM) were designed with the software Primer 3. The glyceraldehyde-3-phosphate dehydrogenase (Gapdh) mRNA was used as the invariant control. Serially diluted samples of pooled cDNA were used as external standards in each run for the quantification. Primer sequences are listed in table 1 below.

[0136] Table 1: Primer sequences used in quantitative PCR experiments

[0137] Statistical analysis

[0138] For each experiment, the data were subjected to one-way analysis of variance followed by the means multiple comparison method of Bonferroni- Dunnett. P < 0.05 was considered as the level of statistical significance.

[0139] RESULTS

[0140] 15(S)-HETE treatment inhibits ovarian adenocarcinoma (OVAD) progression in vivo through macrophages

[0141] The effect of 15(S)-HETE on the tumor burden in a syngeneic ovarian epithelial tumor murine model [Roby et al, 2000] was evaluated. ID8 expressing the firefly luciferase gene (Iuc2) were intra-peritoneally injected into syngeneic female C57BL / 6 mice which resulted in peritoneal carcinomatosis, particularly on peritoneal membrane and diaphragm, and extensive hemorrhagic ascites fluid production after 18 days (Figure 1A). The mice present signs similar to advanced- stage 3 epithelial ovarian cancer, including the development of ascites in the peritoneal cavity and secondary lesions on the peritoneum walls and other organs within the peritoneal cavity [Van Vloten, 2022],

[0142] Treating ID8 tumor-bearing mice with 15(S)-HETE significantly decreased tumor-derived bioluminescence in the abdomen, the peritoneal membrane, the diaphragm and the ascites (Figure 1 B-E) as well as the ascites volume and the weight gain (Figure 1 F).

[0143] To investigate whether 15(S)-HETE treatment impacted macrophage cytotoxic activity, the ability of macrophages from 15(S)-HETE-treated tumor bearing mice to eliminate ID8 tumor cells was evaluated. At day 35 post ID8 injection, the percentage of ID8 cell death was strongly decreased compared to day 18 post ID8 injection, demonstrating that macrophages isolated from untreated-mice ascites at day 35 post ID8 injection have decreased antitumor activity (Figure 1 G). 15(S)-HETE-treatment of tumor-bearing mice did not improve the ability of ascites macrophages to kill ID8 cells at days 7, 18 and 35 post ID8 injection (Figure 1 G), supporting that 15(S)-HETE in vivo antitumor activity cannot be assigned to an increase of the direct cytotoxic activity of macrophages.

[0144] To assess whether the macrophages contribute to 15(S)-HETE’s antitumor activity, the effect of 15(S)-HETE on the antitumor activity in tumor bearing mice selectively depleted of macrophage with clodronate-containing liposomes was determined (Figure 9). Interestingly, macrophage depletion by clodronate i.p. administration inhibited 15(S)-HETE-induced antitumor activity (Figure 1 H) and abrogated the reduced weight gain in 15(S)-HETE-treated mice with clodronate (Figure 11). These results indicated the impact of 15(S)-HETE in tumor development is mediated through the macrophages.

[0145] 15(S)-HETE treatment promotes the differentiation of SPM towards LPM and the LPM maintenance in the peritoneum.

[0146] The influence of 15(S)-HETE treatment on the LPM / SPM proportion in tumor ascites was investigated. As expected, LPM (F4 / 80highMHCIIlow) were more abundant than SPM in the peritoneal cavity of tumor-free mice (Figure 2A). In tumor bearing mice ascites, the proportion of SPM (F4 / 80|OWMHCIIhigh) strongly increased, whereas the proportion of LPM decreased (Figure 2A-B). Surprisingly, 15(S)-HETE treatment restored the LPM / SPM ratio to similar to that of tumor-free mice (Figure 2A).

[0147] SPM had been reported to differentiate into LPM to maintain the resident macrophage proportion during inflammatory situations [Cassado et al, 2015 ; Cain et al, 2013] the impact of 15(S)-HETE on SPM conversion towards LPM was evaluated using established markers [Ghosn et al, 2010 ; Cassado et al, 2015] (Figure 2C). As expected, LPM sorted from ascites of untreated tumor bearing mice expressed high levels of F4 / 80 (Adgrel), CD11 b (Itgam), CD80 and 12 / 15- Lox (Alox15) and low levels of MHCII (Cd74), DC-SIGN (Cd209b) and Dectin-1 (Clec7a), while SPM showed a F4 / 80lowCD11 blowCD80low12 / 15-loxlowMHCIIhighDC-SIGNhighDectin-1highphenotype (Figure 2C). Interestingly, SPM sorted from 15(S)-HETE-treated tumor bearing mice presented an intermediate phenotype characterized by an induction of genes highly expressed in LPM and a decrease of genes weakly expressed in LPM. These results support that 15(S)-HETE treatment promotes the differentiation of SPM into LPM in ovarian adenocarcinoma (OVAD) bearing mice.

[0148] To further confirm the impact of 15(S)-HETE on the differentiation of SPM towards LPM, an adoptive transfer of bone marrow monocytes from CD45.1 mice to tumor-bearing CD45.2 mice, treated or not with 15(S)-HETE, had been conducted. Flow cytometry analysis of peritoneal cells showed that 15(S)-HETE treatment decreased the percentage of CD45.1 + SPM and increased the percentage of CD45.1 + LPM in tumor-bearing mice (Figure 2D), without significantly affecting the total recruited CD45.1 cells (Figure 2E). These results confirmed that SPM can differentiate into LPM in an ovarian cancer model and showed that 15(S)-HETE potentiates this differentiation. C / EBP[3 is a key transcription factor of the SPM-to-LPM differentiation [Cain et al, 2013], the expression of C / EBP[3 and its target genes was evaluated. SPM and LPM from untreated tumor-bearing mice expressed low levels of C / EBP[3 (C / ebpb), Mac2 (Lgals3), 1a-hydroxylase (Cyp27b1) and Pyk2 (Ptk2b) (Figure 2F). 15(S)-HETE treatment increased the mRNA levels of Cebpb, Lgals3, and Cyp27b1 inboth SPM and LPM and increased Ptk2b expression in LPM (Figure 2F). These results further support that15(S)-HETE treatment promotes SPM-to-LPM differentiation through C / EBP[3 expression and activation in ovarian tumor-bearing mice.

[0149] LPM can self-renew in the peritoneum [Cassado et al, 2015], However, 15(S)-HETE treatment did not enhance LPM proliferation measured by BrdU incorporation (Figure 2G). The reduced SPM / LPM ratio upon 15(S)-HETE treatment could be also the consequence of decreased of the Macrophage Disappearance Reaction (MDR) [Narth et al, 1995] . Thus, the expression and the activation of GATA6, a transcription factor for LPM-specific genes involved in their peritoneal adherence [Okabe et al, 2014], were evaluated. As expected, the expression of GATA6 and its target genes, a specific transcription factor for peritoneal LPM-specific genes involved in their peritoneal adherence [Okabe et al, 2014], were observed only in LPM (Figure 2H). 15(S)-HETE treatment strongly increased LPM expression of Gata6, Serpinb2, Selp (CD62p) and Thbsl (Figure 2H). These data demonstrate that 15(S)-HETE treatment inhibits LPM migration from the peritoneum toward the omentum.

[0150] Thus, these data demonstrate that the increase of LPM following 15(S)- HETE treatment is associated with both SPM-to-LPM differentiation and a LPM residency in the peritoneal cavity.

[0151] PPARY mediates 15(S)-HETE treatment-induced C / EBPp and GATA6 activation

[0152] To examine the role of PPARy in 15(S)-HETE-induced differentiation of SPM toward LPM through C / EBPp, PPARy and C / EBP[3 nuclear and cytoplasmic protein levels in macrophages from tumor-bearing mice by image flow cytometry was investigated by image streamX. 15(S)-HETE treatment increased PPARy+and C / EBPp+cells proportion in SPM and LPM (Figure 3A-3D). 15(S)-HETE induced PPARy and C / EBPp nuclear translocation in SPM and LPM (Figure 3B, merge DAPI / PPARy and DAPI / C / EBPP). and PPARy and C / EBPp colocalization in SPM and LPM (Figure 3B, merge PPARy / C / EBPP). 15(S)-HETE increase PPARy and C / EBP[3 protein levels both in SPM and LPM (Figure 3C-D, Figure 10). The involvement of PPARy-GATA6 axis in the 15(S)-HETE-induced macrophage peritoneal retention was evaluated. 15(S)-HETE treatment increased GATA6+cells proportion in LPM, GATA6 protein level was not changed (Figure 3A-D). In SPM only the GATA6 protein level was augmented following 15(S)-HETE treatment (Figure 3A-D), indicating that 15(S)-HETE influence macrophage peritoneal retention through GATA6 by increasing its expression in SPM and the number of GATA6+ cells in LPM. Moreover 15(S)-HETE induced PPARy and GATA6 nuclear co-localization in SPM and LPM (Figure 30, merge PPARy / GATA6 - Figure 10).

[0153] To validate the role of PPARy in C / EBP[3 and GATA6 activation, the C / ebp / 3, Gata6 and their target genes mRNA level in tumor bearing PPARyM’ / ’mice in which the PPARy gene (Pparg) was selectively disrupted in myeloid-derived cells (PPARYM’ / _) was assessed. 15(S)-HETE treatment increased the expression of C / ebp / 3, Gata6 and their target genes in macrophages from PPARyM+ / +tumorbearing mice (Figure 3E-F) but not in macrophages from PPARyM- / - tumorbearing mice.

[0154] Taken together, these results demonstrated that C / EBP[3 and GATA6 play a central role in SPM-to-LPM differentiation and their involvement in LPM peritoneal residence through PPARy activation following 15(S)-HETE treatment during ovarian adenocarcinoma (OVAS).

[0155] 15(S)-HETE treatment favors the presence of antitumor LPM which contribute to counteract cancer immunosuppression.

[0156] To investigate whether LPM have any relevant antitumor phenotype, mRNA levels of representative markers of immunity / tolerance balance in SPM and LPM in ascites of tumor bearing mice was evaluated. Overall, as compared to SPM, LPM highly expressed mRNA levels of Ccl3, Ccl4, Cxcl9 (CXC chemokine ligand 9) and CxcHO (Figure 4A). Although Ccl17 and Ccl22 immunosuppressive chemokines were highly expressed in SPM, they were almost not expressed in LPM Consistently, LPM weakly expressed Cd274 (PDL- 1 ), Pdcd1lg2 (PDL-2 ), ldo-2 (Indoleamine 2,3-Dioxygenase 2), Tgf- / 3 (Tumor Growth Factor-p) and 11-10 immunosuppressive markers (Figure 4A). In the same way, Mmp9 (Matrix Metalloproteinase 9) and Vegf-a (Vascular Endothelial Growth Factor-a) metastatic and angiogenic factors were also lowly expressed in LPM (Figure 4A). Tnf-a (Tumor Necrosis Factor-a) was expressed similarly in SPM and LPM (Figure 4A). Although the 15(S)-HETE treatment did not affect the expression of Ccl3, Ccl4, Cxcl9, CxcHO, Ccl17, Cd274, Mmp9, Vegf-a and Tgf- / 3 in either SPM and LPM, it significantly decreasing the expression of Ccl22, PDL- 2 (Pdcd1lg2), ldo-2 and 11-10 immune tolerance factors (Figure 4A).

[0157] Consistent with LPM accumulation and decreased tolerance signature of LPM following 15(S)-HETE treatment, protein level of CCL3, CCL4, CXCL9, CXCL10 pro-inflammatory chemokines were increased whereas those of CCL22 and CCL17 were decreased in ascites of 15(S)-HETE-treated tumor bearing mice from day 18 post-ID8 injection (Figure 4B). In line with decreased immunosuppressive markers, the IL-10 anti-inflammatory cytokine protein levels was strongly reduced in ascites from 15(S)-HETE-treated tumor bearing mice (Figure 4B). Conversely, protein levels of IL-1 [3 and TNF-a pro-inflammatory cytokines were increased in ascites from 15(S)-HETE-treated tumor bearing mice (Figure 4B).

[0158] Altogether, these data demonstrate that the antitumor effect of 15(S)- HETE treatment is mediated by the increase of immunocompetent LPM frequency in ascites which contributes to counteract cancer immunosuppression.

[0159] 15(S)-HETE treatment improves the effector / regulatory T cell ratio in tumor ascites through a macrophage-dependent mechanism.

[0160] To investigate whether the 15(S)-HETE treatment-induced SPM / LPM balance change increased immune cell recruitment and activation in the tumor microenvironment, the number of immune populations in ascites was evaluated. Although the infiltration of Natural Killer cells (NK1.1 + cells) and macrophages (F4 / 80+cells) in tumor ascites did not change during tumor progression, CD4 (CD3+CD4+CD25-), CD8 (CD3+CD8+) T cells, Tregs (CD4+CD25+FOXP3+) and B cells (CD19+) infiltrations were significantly increased (Figure 5A). Interestingly, although the 15(S)-HETE treatment did not alter the number of macrophages and B cells in ascites, it significantly increased the number of CD4 and CD8 T cells at day 35 post tumor cell injection (Figure 5A). This was accompanied by a strong reduction of FoxP3+ Tregs from day 18 after tumor cell injection (Figure 5A). Because the tumor microenvironment is generally considered to be immunosuppressive, evaluation whether the 15(S)-HETE treatment promoted the activation of CD4 and CD8 T cells was carried out. 15(S)-HETE treatment contributed to polarize CD4 T cells toward the Th1 subset (Figure 5B). Moreover, the proportion of CD183+CD8 T cells, a subset with enhanced cytotoxic potential, was significantly increased in ascites from 15(S)-HETE-treated tumor bearing mice (Figure 5C). Consistent with these findings, T cells (CD3+) isolated of ascites from 15(S)-HETE-treated tumor bearing mice expressed higher mRNA levels of perforin (Prf1), granzyme B (Gzmb) and Fas-ligand (Faslg) (Figure 5D). Altogether these results demonstrate that 15(S)-HETE treatment promotes the recruitment of effective Th1 and cytotoxic T lymphocytes and decreases Tregs frequency in tumor ascites.

[0161] 15(S)-HETE treatment of tumor-bearing mice deficient of the recombinationactivating gene Rag2 did not decrease the tumor burden of peritoneal membrane, diaphragm or ascites (Figure 5E), further supporting the importance of lymphocytes in the antitumor activity of 15(S)-HETE. To investigate whether the impact of 15(S)-HETE on T cells is mediated through macrophages, the recruitment of T regs and the activation of CD4 and CD8 T cells in ascites of tumor bearing mice in which the macrophages were selectively abrogated after clodronate treatment was evaluated (Figure 5F-H). Interestingly, the decrease of Tregs frequency increase of effective Th1 CD4 cells and cytotoxic CD8 T cells in tumor ascites of 15(S)-HETE-treated tumor bearing mice were totally abrogated after clodronate treatment (Figure 5F-H)supporting that 15(S)-HETE treatment promoted a T cell-dependent antitumor response through macrophages.

[0162] The antitumor activity of 15(S)-HETE is mediated by PPARy in macrophages.

[0163] To further dissect how 15(S)-HETE mediates its antitumor effect, the tumor burden in tumor-bearing mice in which the PPARy gene was selectively disrupted in myeloid-derived cells (PPARy1^’7’). Tumor burdens in PPARYM’ / _mice were higher than those in wild type mice (Figure 6A). Consistently LPM were almost absent in ascites from PPARYM’ / _(Figure 6B). Moreover, CD4 and CD8 T cell infiltrations were lower while the infiltration of Tregs was significantly higher in PPARYM' / _mice than in PPARYM+ / +mice (Figure 6C). These data highlight an anti-tumor role of PPARY in macrophages during ovarian adenocarcinoma development.

[0164] Unlike in PPARYM+ / + mice, 15(S)-HETE treatment did not decrease the SPM frequency and did not increase the LPM frequency and the number of CD4 or CD8 T cells, and did not decrease the number of FOXP3+ Tregs in ascites in tumor-bearing PPARYM- / - mice (Figure 6B-C). 15(S)-HETE treatment also did not increase frequencies of Th1 CD4 T cells and cytotoxic CD183+ CD8 T cells in tumor-bearing PPARYM- / - mice (Figure 6D-E).

[0165] The role of PPARY in the antitumor activity of 15(S)-HETE was further supported by decreased tumor burden, restored LPM / SPM ratio and increased expression of C / EBP[3 and GATA6 genes and their target genes in tumor-bearing mice treated with Rosiglitazone, a synthetic PPARY specific agonist [Lehman et al, 1995] (Figure 11 ).

[0166] Altogether these results indicate that PPARY acts in the signaling cascade leading to the inhibition of tumor development, the LPM accumulation in ascites and the enhancement of the effector T cells / Tregs ratio following 15(S)- HETE treatment.

[0167] 15(S)-HETE promotes the differentiation, the peritoneal attachment and attenuates immunosuppressive properties of human ovarian tumor- associated macrophages.

[0168] Three macrophage subsets (Infiltrated, Intermediate and Resident Macrophages), with distinct phenotypes and functions have been recently described in women peritoneal cavity [Ruiz-Alcaraz et al, 2018],

[0169] To validate about findings from the murine model in patient, macrophages proportions in cells isolated from the ascites of ovarian cancer patients by flow cytometry was evaluated. Surprisingly, infiltrated macrophages (CD14interCD16|OW) were most abundant whereas there very few intermediate macrophages (CD14interCD16inter) and no resident macrophages (CD14highCD16high) were identified (Figure 7A-B).

[0170] Consistent with findings in mice, 15(S)-HETE treatment induced expressions of ITGAM (CD11 b) and ALOX15 expression in tumor-associated macrophages while slightly reducing HLADR and did not significantly affect CLEC7A (Dectin-1 ) expression (Figure 7C). Remarkably, 15(S)-HETE treatment also enhanced the expression of C / EBP / 3, GAT AGA genes and their target genes CYP27B1, LGALS3, SELP, SERPINB2, THBS1), supporting that 15(S)-HETE treatment can activate the differentiation of macrophages isolated from human ovarian ascites towards LPM-like macrophages and can favor their maintenance in the peritoneal cavity (Figure 7D). Moreover, 15(S)-HETE treatment decreased mRNA levels of CD274, PDCD1LG2, CCL17, CCL22, and MMP9.. (Figure 7E). These data indicated that 15(S)-HETE had similar effects on human TAMs as on mouse TAMs.

[0171] DISCUSSION

[0172] The growth of ovarian cancer is associated with the development of peritoneal ascites containing pro-inflammatory soluble factors and cellular components which provide a tumor-promoting microenvironment [Ahmed et al, 2013],

[0173] The obtained results demonstrate that 15(S)-HETE treatment inhibits tumor progression in a mouse model of ovarian adenocarcinoma (OVAD) that is mediated through PPARy in macrophages. Consistently, PPARy+ / _mice have an increase susceptibility toward DMBA-mediated breast, skin and ovarian carcinogenesis [Nicol et al, 2004],

[0174] The SPM frequency strongly increases while the percentage of LPM decreases in the peritoneal cavity of untreated tumor-bearing mice. Consistently, SPM mobilization in response to IL-17 in the same murine model of ovarian cancer is associated with tumor progression [Rei et al, 2014], Surprisingly, the 15(S)-HETE treatment modulates the SPM / LPM balance in ascites to closer to that in mice without tumor. In agreement with the ability of SPM to promote ovarian cancer development [Rei et al, 2014], the data characterized SPM as immunosuppressive, which is supported by reports showing that only monocyte- derived alternative activated macrophages express PDL-2 and can induce FoxP3+ Tregs differentiation [Bowman et al, 2016 ; Gundra et al, 2014], Thus, the effect of 15(S)-HETE treatment on the increase of LPM frequency in ascites counteract SPM-mediated immunosuppression. Consistently, 15(S)-HETE treatment promotes the infiltration of CD4+ Th1 T cells and cytotoxic CD8+ T cells in ascites. The weak expression of CCL17 and CCL22 in LPM of 15(S)-HETE- treated mice is correlated with a strong decrease in the Tregs number in ascites. These data demonstrate that 15(S)-HETE enhances the effector T cells / Tregs ratio through the orientation of immunoregulatory SPM toward LPM, which contribute to attract and activate effector immune cells. These observations highlight the involvement of macrophages in T cell-dependent antitumor response upon 15(S)-HETE treatment.

[0175] The results also demonstrate that the SPM-to-LPM differentiation induced by the 15(S)-HETE treatment involves PPARy and C / EBP[3, which is supported by reported close functional and physical links between C / EBP[3 and PPARy29 and crucial role of C / EBP[3 in SPM-to-LPM differentiation [Cain et al, 2013], Furthermore, the results indicate that 15(S)-HETE treatment contributes to the maintenance of LPM in the peritoneal cavity by increasing the expression of GATA6, known to be involved in LPM residency in the peritoneum [Okabe et al, 2014], and adhesion proteins, such as Thbsl , CD62p and Serpinb2, encoded by GATA6-target genes [Schroder et al, 2019], These results are also consistent with the PPARy activation in the preservation of GATA6 expression in bone- marrow derived Mast Cells31 and with the inhibitory effect of 15(S)-HETE treatment on neutrophil migration in inflammatory conditions [Takata et al, 1994], Resident macrophage migration to the omentum has been associated with the spread of ovarian cancer cells to the same site, which worsens the prognosis [Etzerodt et al, 2020], These data strengthen the importance of maintaining LPM in the peritoneal cavity.

[0176] Finally, the results demonstrate that PPARy was a key component in the 15(S)-HETE-triggered signaling cascade that promotes T cell antitumor response. PPARy has a well-known anti-inflammatory role [Tachibana et al, 2008], Nevertheless, several studies have indicated that PPARy has immunostimulatory activities [Van Ginderachter et al. 2006, Schroder et al. 2019, Takata et al 1994], Mice deficient of PPARy selectively in myeloid cells have a decreased CD8+ T effectors to Tregs ratio and an impaired tumor rejection with GM-CSF-secreting tumor-cell vaccines 59. Moreover, PPARy ligands reverse cytotoxic T lymphocyte suppression induced by TAMs and decrease Tregs infiltration [Van Ginderachter et al. 2006, Takata et al 1994],

[0177] In conclusion, the results clearly demonstrate that 15(S)-HETE has an antitumor activity in a murine model of OVAD. In particular, the results demonstrate that the antitumor activity is mediated through promoting the differentiation of SPM to LPM and maintaining LPM in the peritoneum. LPM contribute to counteract cancer immunosuppression and to attract effector immune T cells (Figure 8). These results also clearly demonstrate the critical role of compound activating PPARy, for example 15(S)-HETE, for example of macrophages, triggered the inhibition of OVAD development, demonstrating and supporting the use of compound activating PPARy, for example PPARy agonists in anti-cancer therapy.

[0178] This example clearly demonstrate that compound activating the peroxisome proliferator-activated gamma receptor (PPARy), for example agonist of PPARy, allows to inhibit of ovarian adenocarcinoma development.

[0179] This example also clearly demonstrate that compound activating the peroxisome proliferator-activated gamma receptor (PPARy), for example agonist of PPARy, allows the prevention and / or treatment of cancer.

[0180] This example further clearly demonstrate that compound activating the peroxisome proliferator-activated gamma receptor (PPARy), for example agonist of PPARy, allows the prevention and / or treatment of cancer involving small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM), for example ovarian cancer, pancreatic cancer, colon cancer, lymphoma.

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Claims

Claims1. Compound activating the peroxisome proliferator-activated gamma receptor (PPARy) for use in the prevention and / or treatment of cancer involving small peritoneal macrophages (SPM) and large peritoneal macrophages (LPM).

2. Compound for use according to claim 1 , wherein the compound is selected from the group comprising agonist of the peroxisome proliferator-activated gamma receptor (PPARy).

3. Compound for use according to claim 1 , wherein the compound is selected from the group comprising pioglitazone, rosiglitazone, glitazones, troglitazone, ciglitazone, farglitazar, saroglitazar, ATX08-001 , Ged-0507- 34-Levo, T3D-959, IVA-337, KDT-501 , CS-038, CHS-131 , S26948, INT131 docosahexaenoic acid, eicosapentaenoic acid, inolitazone dihydrochloride (RS5444), 9- hydroxyoctadecadienoic acid; 13- hydroxyoctadecadienoic acid, 15-deoxy 12,14-prostaglandin J2, prostaglandin PGJ2, 15S-Hydroxyeicosatetraenoic acid (15S-HETE)4. Compound for use according to any one of the preceding claims wherein the compound is in combination with anti-cancer drug, anti-angiogenic drug, anti-inflammatory drug, anti-oxidative drug, immunotherapy.

5. Compound for use according to any one of the preceding claims wherein the cancer is selected from the group comprising ovarian cancer, pancreatic cancer, colon cancer, lymphoma, uterus cancer, cervix cancer, colorectal cancer, stomach cancer, pancreas cancer, breast cancer and liver cancer.

6. Compound for use according to any one of the preceding claims wherein the cancer is ovarian adenocarcinoma.

7. A pharmaceutical composition comprising a compound as defined according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier, diluent or excipient, for use in the prevention and / or treatment of cancer.

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