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.
Clinical trial identification
Legal entity responsible for the study
University Hospital of Besançon France
All authors have declared no conflicts of interest.