Regulation of T cell antitumor immune response by tumor induced metabolic stress

Adaptive T cell immune response is essential for tumor growth control. The efficacy of immune checkpoint inhibitors is regulated by intratumoral immune response. The tumor microenvironment has a major role in adaptive immune response tuning. Tumor cells generate a particular metabolic environment in comparison to other tissues. Tumors are characterized by glycolysis, hypoxia, acidosis, amino acid depletion and fatty acid metabolism modification. Such metabolic changes promote tumor growth, impair immune response and lead to resistance to therapies. This review will detail how these modifications strongly affect CD8 and CD4 T cell functions and impact immunotherapy efficacy

Production of Adenosine by Ectonucleotidases: A Key Factor in Tumor Immunoescape

It is now well known that tumor immunosurveillance contributes to the control of cancer growth. Many mechanisms can be used by cancer cells to avoid the antitumor immune response. One such mechanism relies on the capacity of cancer cells or more generally of the tumor microenvironment to generate adenosine, a major molecule involved in antitumor T cell response suppression. Adenosine is generated by the dephosphorylation of extracellular ATP released by dying tumor cells. The conversion of ATP into adenosine is mediated by ectonucleotidase molecules, namely, CD73 and CD39. These molecules are frequently expressed in the tumor bed by a wide range of cells including tumor cells, regulatory T cells, Th17 cells, myeloid cells, and stromal cells. Recent evidence suggests that targeting adenosine by inhibiting ectonucleotidases may restore the resident antitumor immune response or enhance the efficacy of antitumor therapies. This paper will underline the impact of adenosine and ectonucleotidases on the antitumor response

Roles of myeloïd derived suppressor cells and Th17 lymphocytes in cancer

Le système immunitaire joue un double rôle dans le cancer: il peut non seulement supprimer la croissance tumorale en détruisant les cellules cancéreuses, mais aussi promouvoir la progression de la tumeur en sélectionnant les cellules tumorales ou en créant un microenvironnement tumoral immunosuppresseur. Au cours de ma thèse, je me suis intéressée à deux populations du système immunitaire : les MDSC (Myeloïd Derived Suppressor Cells) et les lymphocytes Th17. Dans ce travail, nous avons exploré les mécanismes impliqués dans l’activation et dans les fonctions suppressives de ces deux populations cellulaires au cours de la croissance tumorale. Tout d’abord, nous avons montré que les cellules tumorales activaient les MDSC en libérant des exosomes exprimant HSP72 à leur surface. HSP72 à la surface des exosomes permet l’activation de STAT3 via la voie de signalisation TLR2/Myd88 dans les MDSC et favorise leur fonction suppressive. Le facteur de transcription STAT3 joue aussi un rôle fondamental dans la différenciation des lymphocytes Th17. Le rôle des lymphocytes Th17 est controversé dans la croissance tumorale. Nous avons découvert que les lymphocytes Th17 exprimaient les ectonucléotidases CD39 et CD73 soutenant ainsi leur fonction suppressive. L'expression des ectonucléotidases est dépendante de l’activation de STAT3 par l’IL-6 et de l’inhibition de Gfi-1 par le TGFβ lors de leur différenciation.Immune system plays a dual role in cancer: it can not only suppress tumor growth by destroying cancer cells, but also promote tumor progression by selecting immunoresistant tumor cells or by establishing an immunosuppressive microenvironment.During my thesis, I focused on two populations of the immune system: MDSC (myeloid derived suppressor cells) and Th17 lymphocytes. In this work, we explored the mechanisms involved in the activation of suppressive functions of these two cell populations during tumor growth. First, we showed that tumor cells activated MDSC by releasing exosomes that express HSP72 on their surface. HSP72 on exosomes surface induces STAT3 activation via Myd88/TLR2 signaling pathway in MDSC and promotes their suppressive function. The transcription factor STAT3 also plays a fundamental role in Th17 cells differentiation. The role of Th17 cells is controversial in tumor growth. We reported that Th17 cells express CD39 and CD73 ectonucleotidases and thereby supporting their suppressive function. The expression of ectonucleotidases is dependent on the activation of STAT3 by IL-6 and inhibition of Gfi-1 by TGFβ during their differentiation

Rôles des cellules myéloïdes suppressives et des lymphocytes Th17 dans le cancer

Le système immunitaire joue un double rôle dans le cancer: il peut non seulement supprimer la croissance tumorale en détruisant les cellules cancéreuses, mais aussi promouvoir la progression de la tumeur en sélectionnant les cellules tumorales ou en créant un microenvironnement tumoral immunosuppresseur. Au cours de ma thèse, je me suis intéressée à deux populations du système immunitaire : les MDSC (Myeloïd Derived Suppressor Cells) et les lymphocytes Th17. Dans ce travail, nous avons exploré les mécanismes impliqués dans l activation et dans les fonctions suppressives de ces deux populations cellulaires au cours de la croissance tumorale. Tout d abord, nous avons montré que les cellules tumorales activaient les MDSC en libérant des exosomes exprimant HSP72 à leur surface. HSP72 à la surface des exosomes permet l activation de STAT3 via la voie de signalisation TLR2/Myd88 dans les MDSC et favorise leur fonction suppressive. Le facteur de transcription STAT3 joue aussi un rôle fondamental dans la différenciation des lymphocytes Th17. Le rôle des lymphocytes Th17 est controversé dans la croissance tumorale. Nous avons découvert que les lymphocytes Th17 exprimaient les ectonucléotidases CD39 et CD73 soutenant ainsi leur fonction suppressive. L'expression des ectonucléotidases est dépendante de l activation de STAT3 par l IL-6 et de l inhibition de Gfi-1 par le TGFb lors de leur différenciation.Immune system plays a dual role in cancer: it can not only suppress tumor growth by destroying cancer cells, but also promote tumor progression by selecting immunoresistant tumor cells or by establishing an immunosuppressive microenvironment.During my thesis, I focused on two populations of the immune system: MDSC (myeloid derived suppressor cells) and Th17 lymphocytes. In this work, we explored the mechanisms involved in the activation of suppressive functions of these two cell populations during tumor growth. First, we showed that tumor cells activated MDSC by releasing exosomes that express HSP72 on their surface. HSP72 on exosomes surface induces STAT3 activation via Myd88/TLR2 signaling pathway in MDSC and promotes their suppressive function. The transcription factor STAT3 also plays a fundamental role in Th17 cells differentiation. The role of Th17 cells is controversial in tumor growth. We reported that Th17 cells express CD39 and CD73 ectonucleotidases and thereby supporting their suppressive function. The expression of ectonucleotidases is dependent on the activation of STAT3 by IL-6 and inhibition of Gfi-1 by TGFb during their differentiation.DIJON-BU Doc.électronique (212319901) / SudocSudocFranceF

Oxysterols regulate CD4+ T cell trafficking during experimental autoimmune encephalomyelitis

Perturbation of steroids pathways has been linked to inflammation and chronic diseases. Oxysterols, oxidised forms of cholesterol, are essential for bile synthesis biosynthesis and sterol transportation. In addition to their basic metabolic properties, oxysterols modulate immune response and control trafficking of immune cells such as B lymphocytes and macrophages. Furthermore, serum oxysterols levels have been proposed as putative candidate biomarkers for neurological diseases such as Multiple sclerosis (MS). The enzyme cholesterol 25 hydroxylase (ch25h) is the rate limiting step to synthetize the oxysterol 7,25-dihydroxycholesterol (725-OHC) from cholesterol. We here report, using the MS murine model experimental autoimmune encephalomyelitis (EAE), that deletion of ch25h attenuated EAE disease course by dampening pathogenic T lymphocytes trafficking to the central nervous system (CNS). While systemic immune response is preserved in the absence of ch25h, IL-17 producing CD4+ T helper (TH17) cells accumulate in the draining lymph nodes. Furthermore, TH17 cells migrate towards 725-OHC in an Epstein-Barr virus-induced G-protein coupled receptor 2 (ebi2) dependent-manner. Collectively, our results reveal a critical involvement for oxysterols in migration of distinct subset of CD4+ T lymphocytes thus supporting a pro-inflammatory role for oxysterols during EAE

Oxysterols regulate encephalitogenic CD4⁺ T cell trafficking during central nervous system autoimmunity

Perturbation of steroids pathways is linked to inflammation and chronic diseases, however the underlying mechanism remains unclear. Oxysterols, oxidized forms of cholesterol, are not only essential for bile synthesis and sterol transportation but have recently been shown to contribute to the immune response. In addition, serum oxysterols levels have been proposed as suitable candidate biomarkers for neurological diseases such as multiple sclerosis (MS). However how oxysterols modulate adaptive immunity is unknown and their functions in autoimmunity have not been investigated. The enzyme cholesterol 25 hydroxylase (Ch25h) is the rate limiting step to synthesize the oxysterol 7α,25-dihydroxycholesterol (7α,25-OHC) from cholesterol. We here report, using the MS murine model experimental autoimmune encephalomyelitis (EAE), that Ch25h deletion significantly attenuated EAE disease course by limiting trafficking of pathogenic CD4(+) T lymphocytes to the central nervous system (CNS). Mechanistically, we show a critical involvement for oxysterols in recruiting leukocytes into inflamed tissues and propose that 7α,25-OHC preferentially promotes the migration of activated CD44(+)CD4(+) T cells by binding the G protein-coupled receptor called Epstein-Barr virus induced gene 2 (EBI2). Collectively, our results support a pro-inflammatory role for oxysterols during EAE and identify oxysterols as a potential therapeutic target to treat autoimmune diseases

Dacarbazine-mediated upregulation of NKG2D ligands on tumor cells activates NK and CD8 T cells and restrains melanoma growth.

International audienceDacarbazine (DTIC) is a cytotoxic drug widely used for melanoma treatment. However, the putative contribution of anticancer immune responses in the efficacy of DTIC has not been evaluated. By testing how DTIC affects host immune responses to cancer in a mouse model of melanoma, we unexpectedly found that both natural killer (NK) and CD8(+) T cells were indispensable for DTIC therapeutic effect. Although DTIC did not directly affect immune cells, it triggered the upregulation of NKG2D ligands on tumor cells, leading to NK cell activation and IFNγ secretion in mice and humans. NK cell-derived IFNγ subsequently favored upregulation of major histocompatibility complex class I molecules on tumor cells, rendering them sensitive to cytotoxic CD8(+) T cells. Accordingly, DTIC markedly enhanced cytotoxic T lymphocyte antigen 4 inhibition efficacy in vivo in an NK-dependent manner. These results underscore the immunogenic properties of DTIC and provide a rationale to combine DTIC with immunotherapeutic agents that relieve immunosuppression in vivo

Interleukin-27 drives oxysterol production that regulate the adaptive Immune response

Oxysterols, oxidized forms of cholesterol, have pleiotropic roles on the immune response aside from their involvement in lipid metabolism. The oxysterols 25-hydroxycholesterol (25-OHC) and 725-dihydroxycholesterol (725-OHC) regulate antiviral immunity and immune cell chemotaxis. However their physiological effects on adaptive immune response in particular on CD4+ T lymphocytes are largely unknown. Here we assessed oxysterol levels in subset of CD4+ T cells and demonstrated that 25-OHC and transcript levels of its synthesizing enzyme, cholesterol 25 hydroxylase (Ch25h), were specifically increased in IL-27-induced Type 1 regulatory T (TR1) cells. We further showed that 25-OHC acts as negative regulator of TR1 cells in particular of IL-10 secretion via LXR signaling. Not only do these findings unravel novel molecular mechanisms accounting for IL-27 signaling but they also highlight lipids as critical modulators of adaptive immunity