Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity.
Fiche publication
Date publication
juillet 2016
Journal
Cancer research
Auteurs
Membres identifiés du Cancéropôle Est :
Pr ADOTEVI Olivier, Pr BORG Christophe, Dr GODET Yann, Pr PIVOT Xavier, Dr ROYER Bernard, Dr CURTIT Elsa, Dr MANSI Laura, Dr THIERY-VUILLEMIN Antoine, Dr MOUILLET Guillaume
Tous les auteurs :
Beziaud L, Mansi L, Ravel P, Marie-Joseph EL, Laheurte C, Rangan L, Bonnefoy F, Pallandre JR, Boullerot L, Gamonet C, Vrecko S, Queiroz L, Maurina T, Mouillet G, Hon TN, Curtit E, Royer B, Gaugler B, Bayry J, Tartour E, Thiery-Vuillemin A, Pivot X, Borg C, Godet Y, Adotévi O
Lien Pubmed
Résumé
The 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.
Mots clés
Animals, Carcinoma, Renal Cell, immunology, Cell Line, Tumor, Everolimus, pharmacology, Female, Humans, Immunosuppressive Agents, pharmacology, Interferon-gamma, biosynthesis, Interleukin-2, biosynthesis, Kidney Neoplasms, immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, T-Lymphocytes, drug effects, TOR Serine-Threonine Kinases, antagonists & inhibitors, Telomerase, immunology, Th1 Cells, immunology
Référence
Cancer Res.. 2016 Jul;76(14):4100-12