3988 - Basal NK activity and early Treg function inhibition predicts Nivolumab responsiveness in metastatic renal cancer patients (REVOLUTION) trial.

Background

PD-1 blockade on Regulatory T cells (Tregs) increases resistance of effector T cells to Tregs suppression and directly reduces in vitro Tregs suppressive function. NKs expressed PD-1 and engagement of PD-1 reduces their cytolysis potential. and the effect of CXCR4 antagonism are evaluated on ex vivo Tregs and NKs.

Methods

43 Nivolumab treated-mRCC patients, 20 other than ICI treated –mRCC (CTR) and 15 Healthy donors (HD) were enrolled. 29 patients underwent first clinical evaluation at 3 months resulting in 23 patients with Objective Response (OR) and 6 in progression (PD). Tregs (CD4+CD25+CD127lowFOXP3+) and NKs (CD3-CD56+CD107a+) phenotype and function were evaluated at day 0, 14, 28, 90, and 180. CFSE-T-effector proliferation-Treg dependent and CD107a externalization toward K562 as NK function were evaluated.

Results

29 patients underwent first clinical evaluation at 3 months resulting in 23 patients with Objective Response (OR) and 6 in progression (PD). Higher NKG2D was reported on CD3-CD56dim cells from OR patients as compared to PD patients (p = 0.0054). A clear reduction in NK basal activity was detected at T0 in 3 months progressed Nivolumab treated patients (p = 0.029). Percent of basal Tregs CD4+CD25+CD127lowFOXP3+ was robustly high (p < 0.001) and CD8/Tregs ratio low (p < 0.001) in 63 mRCC patients as compared to 15 HD. Significant lower PD-1 in Treg cells was observed at 3 months treatment in OR patients ( p = 0.048) and a decrease of HELIOS was showed in PD vs OR patients at time 0 (p = 0.017). Ex vivo Tregs were significantly inhibited by CXCR4 antagonism at day 14 in OR patients (p = 0.0024). Characterization of primary RCCs tumor microenvironment and proteomic/ cyto-chemokines profile are ongoing.

Conclusions

Basal NK activity and early detection (2 weeks) of CXCR4 dependent reversal of Treg suppressive activity significantly discriminates mRCC Nivolumab responding patients.

Clinical trial identification

NCT03891485.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Transcan 2016.

Disclosure

All authors have declared no conflicts of interest.