| Added by | mollevi |
|---|---|
| Last modified by | jacques.colinge |
| Group name | EquipeJC |
| Item Type | Journal Article |
| Title | Rapalogs efficacy relies on the modulation of antitumor T cell immunity |
| Creator | Beziaud et al. |
| Author | L. Beziaud |
| Author | L. Mansi |
| Author | P. Ravel |
| Author | E. Lauret Marie-Joseph |
| Author | C. Laheurte |
| Author | L. Rangan |
| Author | F. Bonnefoy |
| Author | J. R. Pallandre |
| Author | L. Boullerot |
| Author | C. Gamonet |
| Author | S. Vrecko |
| Author | L. Queiroz |
| Author | T. Maurina |
| Author | G. Mouillet |
| Author | T. Nguyen Tan Hon |
| Author | E. Curtit |
| Author | B. Royer |
| Author | B. Gaugler |
| Author | J. Bayry |
| Author | E. Tartour |
| Author | A. Thierry-Vuillemin |
| Author | X. Pivot |
| Author | C. Borg |
| Author | Y. Godet |
| Author | O. Adotevi |
| Abstract | 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. |
| Publication | Cancer Res |
| Date | May 17 2016 |
| Journal Abbr | Cancer research |
| DOI | 10.1158/0008-5472.CAN-15-2452 |
| ISSN | 1538-7445 (Electronic) 0008-5472 (Linking) |
| Tags | original |
| Date Added | 2018/11/14 - 11:48:35 |
| Date Modified | 2019/05/14 - 21:00:27 |
| Notes and Attachments | (Note) (Note) 27197194 (Attachment) |
Institut de Recherche en Cancérologie de
