Abstract
The rapalogs everolimus that inhibit mTOR signaling are used as anti-proliferative drugs in metastatic renal cell carcinoma (mRCC). The influence of immune modulation mediated by everolimus on its antitumor efficacy is poorly investigated. We performed a prospective immunomonitoring study in 23 mRCC patients treated with everolimus. Study showed that everolimus promoted high expansion of FoxP3+Helios+Ki67+ regulatory CD4 T cells (Tregs). Everolimus exposure strongly enhanced the suppressive functions of patients' Tregs. Paradoxically, a concurrent activation of tumor-specific Th1 immunity also occurred during everolimus treatment. Interestingly, an early change of the Tregs/antitumor Th1 balance can differentially shapes the treatment efficacy. Thus, patients presenting a shift towards Tregs decrease and high expansion of antitumor Th1 response had a better survival (PFS: 13.2 months vs 4.1 months P = 0.02). At the time of disease progression upon everolimus treatment, the majority of mRCC patients totally lost the anti-tumor Th1 response in favor to a marked increase of circulating Tregs. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T cell immunity on the clinical effectiveness of everolimus. So there is a strong rational to combine everolimus with Tregs or immune checkpoint blockade to shift host immune responses toward protective antitumor immunity.
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