The rapalogs everolimus and temsirolimus that inhibit mTOR signaling are used as anti-proliferative drugs in several cancers. Here we investigated the influence of rapalogs-mediated immune modulation on their antitumor efficacy. Studies in metastatic renal cell carcinoma (mRCC) 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, 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 towards 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 cells 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 research. 2016 May 17 [Epub ahead of print]
Laurent Beziaud, Laura Mansi, Patrice Ravel, Elodie Lauret Marie-Joseph, Caroline Laheurte, Laurie Rangan, Francis Bonnefoy, Jean René Pallandre, Laura Boullerot, Clémentine Gamonet, Sindy Vrecko, Lise Queiroz, Tristan Maurina, Guillaume Mouillet, Thierry Nguyen Tan Hon, Elsa Curtit, Bernard Royer, Beatrice Gaugler, Jagadeesh Bayry, Eric Tartour, Antoine Thierry-Vuillemin, Xavier Pivot, Christophe Borg, Yann Godet, Olivier Adotévi
UMR1098, University of Bourgogne France-Comté, Department of Medical Oncology, INSERM UMR1098., IRCM-INSERM U1194, Institut de Recherche en Cancérologie de Montpellier., UMR1098, INSERM., UMR1098, EFS Bourgogne France-Comté, UMR1098, INSERM., UMR1098, INSERM., UMR INSERM-UFC-EFS 1098, Université de Franche Comté, UMR1098, INSERM., UMR1098, INSERM., UMR1098, INSERM., UMR1098, INSERM., Department of Medical Oncology, University Hospital of Besançon., Department of Medical Oncology, University Hospital of Besançon., Department of Medical Oncology, University Hospital Besançon., Department of Medical Oncology, University Hospital Besançon., Department of Pharmacology, Univeristy Hospital of Besançon., UMR1098, INSERM., Immunopathologie et immunointervention thérapeutique, INSERM U872, Centre de recherche des Cordeliers, Université Pierre et Marie Curie and Université Paris Descartesn UMR-santé 872., Department of Biological Immunology, Hôpital Européen Georges Pompidou., Department of Medical Oncology, Univeristy Hospital of Besançon., Department of Medical Oncology, Univeristy Hospital of Besançon., University of Bourgogne Franche-Comté, INSERM UMR1098., INSERM UMR1098, University of Bourgogne France-Comté, Medical Oncology, INSERM, UMR1098 .