Abstract
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.
Highlights
MTOR protein is a conserved serine/threonine kinase involved in the regulation of cell growth, metabolism, and apoptosis [1]
A prospective immunomonitoring study was conducted in 23 metastatic renal cell carcinoma (mRCC) patients treated with everolimus
We showed that CD8 T-cell depletion significantly reduced the antitumor efficacy of temsirolimus or everolimus against B16F10 cells transfected with ovalbumin (B16-OVA) (P < 0.05; Fig. 5A)
Summary
MTOR protein is a conserved serine/threonine kinase involved in the regulation of cell growth, metabolism, and apoptosis [1]. It exerts its physiologic functions through two distinct complexes named mTOR complex 1 (mTORC1) and 2 (mTORC2) downstream of the PI3K/AKT pathway [1]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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