8 research outputs found
Impact of mTOR inhibtors on antitumor T cell immunity
La voie de signalisation mTOR (mammalian Target Of Rapamycin) joue un rĂŽle central dans la croissance cellulaire, le mĂ©tabolisme, et l'homĂ©ostasie des lymphocytes T (LT). Lors de la transplantation d'organes, l'administration de rapamycine, un inhibiteur de mTOR (mTORi), bloque l'activation des LT et promeut la polarisation des lymphocytes T CD4 rĂ©gulateur (Treg). En cancĂ©rologie, des mTORi sont utilisĂ©s pour leur action inhibitrice sur la prolifĂ©ration et l'angiogenĂšse tumorales. Cependant l'immunosuppression via l'induction de Treg nĂ©cessaire Ă la prĂ©vention du rejet de greffe pourrait ĂȘtre dĂ©lĂ©tĂšre pour la rĂ©ponse anti-tumorale. Notre hypothĂšse est que l'efficacitĂ© clinique des mTORi serait Ă©galement dĂ©pendante de la modulation de l'immunitĂ© adaptative T induite par ces traitements chez les patients atteints de cancer.Au cours de cette thĂšse, nous avons abordĂ© cette question immunologique dans une cohorte prospective de patients atteints de cancer rĂ©nal mĂ©tastatique (mRCC) traitĂ©s par Ă©vĂ©rolimus. L'analyse du taux de Treg et de la rĂ©ponse spontanĂ©e T CD4 Thl anti-tumorale (anti-tĂ©lomĂ©rase TERT) par Elispot-IFN-y a Ă©tĂ© effectuĂ©e au moment de l'inclusion des patients et tous les deux mois aprĂšs le dĂ©but du traitement. Nous avons observĂ© chez la majoritĂ© des patients une augmentation du taux de Treg aprĂšs traitement par Ă©vĂ©rolimus. Ces Treg expriment HĂ©lios, suggĂ©rant un phĂ©notype Treg naturel. La frĂ©quence et la qualitĂ© de la rĂ©ponse Thl anti-TERT sont Ă©galement augmentĂ©es suite au traitement. Nous avons montrĂ© que conjointement ces deux paramĂštres immunologiques corrĂšlent avec l'efficacitĂ© clinique du traitement. Les patients prĂ©sentant prĂ©cocement une diminution des Treg associĂ©e Ă une augmentation des Thl anti-TERT ont une meilleure survie par rapport aux patients dont les paramĂštres immunitaires ne variaient pas, ou variaient dans une mĂȘme direction (13,2 mois vs 8 et 4 mois). De plus, au moment de la progression la plupart des patients perdaient leur rĂ©ponse Thl anti-TERT, et cet effet Ă©tait associĂ© Ă une augmentation des Treg. Les Treg traitĂ©s par mTORi in vitro inhibent plus fortement la prolifĂ©ration de LT allogĂ©niques, par un mĂ©canisme contact dĂ©pendant. Par l'utilisation d'anticorps monoclonaux dĂ©plĂ©tant les LT chez la souris et par l'utilisation de souris DEREG, nous avons montrĂ© que la prĂ©sence de Treg in vivo altĂšre l'efficacitĂ© anti-tumorale des mTORi, par un mĂ©canisme impliquant l'inhibition des rĂ©ponses T CD8 anti-tumorales. En consĂ©quence, l'efficacitĂ© des mTORi a pu ĂȘtre augmentĂ©e par sa combinaison avec des agents bloquant les Treg. En addition, l'administration de temsirolimus amĂ©liore l'efficacitĂ© anti-tumorale d'un vaccin thĂ©rapeutique, en favorisant la diffĂ©renciation des LT CD8 anti-tumoraux centraux mĂ©moires (CD62L+CD127+) et prĂ©curseurs mĂ©moires (CD127+KLRGl'°) induits par la vaccination.En conclusion, ces Ă©tudes ont montrĂ© pour la premiĂšre fois le rĂŽle de l'immunitĂ© T anti-tumorale sur l'efficacitĂ© clinique des mTORi et soulignent ainsi l'intĂ©rĂȘt potentiel de combiner les mTORi avec des immunothĂ©rapies anti-tumoralesThe mammalian Target of Rapamycin (mTOR) pathway plays a central role in the regulation of cell growth andmetabolism, and is involved in oncogenesis. Everolimus and temsirolimus are two mTOR inhibitors (mTORi) approvedfor renal and breast carcinoma treatments. However, accumulating evidence highlights a central role for mTOR pathwayin T cell immunity. We showed that 21 out of 23 metastatic renal cell carcinoma patients under everolimus treatmenthad an increase of Tregs atter everolimus treatment. Paradoxically, strong antitumor Th 1 responses were detected andthen greatly decreased at the time of disease progression when high expansion of Tregs occurred. Furthermore, weidentified three immune groups based on the early modulation of both Treg and anti-tumor Thl cells and found thatpatients with {low Tregs plus high anti-tumor Thl cells} showed the best survival. In vitro, mTORi-exposed Tregs highlysuppressed T cell proliferation and Thl-associated cytokines production. We showed in vivo that T cells depletiondifferentially modulated the antitumor efficacy of mTORi. Although anti-mTOR effect was loss in B16-OVA-bearingmice lacking CD8 T cells, CD4 T depletion increased mTORi efficacy. The studies conducted in mice demonstratedthat the presence of Tregs in vivo altered the responses to mTORi via a mechanism involving the inhibition of antitumorCD8 T cell responses. Finally the efficacy of mTORi was improved by combination with Tregs depleting agents andvaccines. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T cell immunity onthe clinical effectiveness of mTQRi and prompt their association with immunotherapies
Synergistic CD40 signaling on APCs and CD8 T cells drives efficient CD8 response and memory differentiation
International audienceThe role of CD4 help during CD8 response and memory differentiation has been clearly demonstrated in different experimental models. However, the exact mechanisms of CD4 help remain largely unknown and preclude replacement therapy to develop. Interestingly, studies have shown that administration of an agonist aCD40ab can substitute CD4 help in vitro and in vivo, whereas the targets of this antibody remain elusive. In this study, we address the exact role of CD40 expression on APCs and CD8 T cells using aCD40ab treatment in mice. We demonstrate that aCD40 antibodies have synergetic effects on APCs and CD8 T cells. Full efficiency of aCD40 treatment requires CD40 expression on both populations: if one of these cell populations is CD40-deficient, the CD8 T cell response is impaired. Most importantly, direct CD40 signaling on APCs and CD8 T cells affects CD8 T cell differentiation differently. In our model, CD40 expression on APCs plays an important but dispensable role on CD8 T cell expansion and effector functions during the early phase of the immune response. Conversely, CD40 on CD8 T cells is crucial and nonredundant for their progressive differentiation into memory cells. Altogether, these results highlight that CD40-CD40L-dependent and independent effects of CD4 help to drive a complete CD8 T cell differentiation
Metabolic dependencies of metastasis-initiating cells in female breast cancer
Abstract Understanding the mechanisms that enable cancer cells to metastasize is essential in preventing cancer progression. Here we examine the metabolic adaptations of metastasis-initiating cells (MICs) in female breast cancer and how those shape their metastatic phenotype. We find that endogenous MICs depend on the oxidative tricarboxylic acid cycle and fatty acid usage. Sorting tumor cells based upon solely mitochondrial membrane potential or lipid storage is sufficient at identifying MICs. We further identify that mitochondrially-generated citrate is exported to the cytoplasm to yield acetyl-CoA, and this is crucial to maintaining heightened levels of H3K27ac in MICs. Blocking acetyl-CoA generating pathways or H3K27ac-specific epigenetic writers and readers reduces expression of epithelial-to-mesenchymal related genes, MIC frequency, and metastatic potential. Exogenous supplementation of a short chain carboxylic acid, acetate, increases MIC frequency and metastasis. In patient cohorts, we observe that higher expression of oxidative phosphorylation related genes is associated with reduced distant relapse-free survival. These data demonstrate that MICs specifically and precisely alter their metabolism to efficiently colonize distant organs
Modulation of antitumor T cell responses induced by everolimus in metastatic Renal Cell Carcinoma patients.
Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells
International audienceTelomerase is a prototype-shared tumor Ag and represents an attractive target for anticancer immunotherapy. We have previously described promiscuous and immunogenic HLA-DR-restricted peptides derived from human telomerase reverse transcriptase (hTERT) and referred as universal cancer peptide (UCP). In nonsmall cell lung cancer, the presence of spontaneous UCP-specific CD4 T cell responses increases the survival of chemotherapy-responding patients. However, the precise mechanisms of hTERT's uptake, processing, and presentation on MHC-II molecules to stimulate CD4 T cells are poorly understood. In this work, by using well-characterized UCP-specific CD4 T cell clones, we showed that hTERT processing and presentation on MHC-II involve both classical endolysosomal and nonclassical cytosolic pathways. Furthermore, to our knowledge, we demonstrated for the first time that hTERT's internalization by dendritic cells requires its interaction with surface heparan sulfate proteoglycans. Altogether, our findings provide a novel mechanism of tumor-specific CD4 T cell activation and will be useful for the development of novel cancer immunotherapies that harness CD4 T cells
Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells
Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity
International audienceThe rapalogs everolimus and temsirolimus that inhibit mTOR signaling are used as antiproliferative drugs in several cancers. Here we investigated the influence of rapalogs-mediated immune modulation on their antitumor efficacy. Studies in metastatic renal cell carcinoma patients showed that everolimus promoted high expansion of FoxP3 (+)Helios(+)Ki67(+) regulatory CD4 T cells (Tregs). In these patients, rapalogs strongly enhanced the suppressive functions of Tregs, mainly in a contact-dependent manner. Paradoxically, a concurrent activation of spontaneous tumor-specific Th1 immunity also occurred. Furthermore, a high rate of Eomes(+)CD8(+) T cells was detected in patients after a long-term mTOR inhibition. We found that early changes in the Tregs/antitumor Th1 balance can differentially shape the treatment efficacy. Patients presenting a shift toward decreased Tregs levels and high expansion of antitumor Th1 cells showed better clinical responses. Studies conducted in tumor-bearing mice confirmed the deleterious effect of rapalogs-induced Tregs via a mechanism involving the inhibition of antitumor T-cell immunity. Consequently, the combination of temsirolimus plus CCR4 antagonist, a receptor highly expressed on rapalogs-exposed Tregs, was more effective than monotherapy. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T-cell immunity on the clinical effectiveness of rapalogs and prompt their association with immunotherapies. Cancer Res; 76(14); 4100-12. ©2016 AACR