The efficacy of everolimus relies on a modulation of adaptative anti tumor T cell immunity

Background

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.

Methods

We performed a prospective immunomonitoring study in 23 mRCC patients treated with everolimus.

Results

Study showed that everolimus promoted high expansion of FoxP₃⁺Helios⁺Ki67⁺ regulatory CD4 T cells (T_regs). Everolimus exposure strongly enhanced the suppressive functions of patients' T_regs. Paradoxically, a concurrent activation of tumor-specific Th1 immunity also occurred during everolimus treatment. Interestingly, an early change of the T_regs/antitumor Th1 balance can differentially shapes the treatment efficacy. Thus, patients presenting a shift towards T_regs 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 T_regs.

Conclusions

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 T_regs 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

Funding

N/A

Disclosure

All authors have declared no conflicts of interest.