KIR2DL2/DL3+NKs and Helios+Tregs in peripheral blood predict nivolumab response in patients with metastatic renal cell cancer.

ABSTRACT

PURPOSE: To identify predictive factors of nivolumab sensitivity, peripheral blood NKs and Tregs were evaluated in patients with metastatic renal cell carcinoma (mRCC) enrolled in the REVOLUTION trial. EXPERIMENTAL DESIGN: 57 mRCCs being treated with nivolumab, as at least second-line of therapy (REV), and 62 healthy donors (HDs) were longitudinally evaluated (0-1-3-6-12 months) for peripheral NKs and Tregs, phenotype and function. Multivariable logistic regression were conducted to identify the independent predictors. The .632+ internal cross-validation was used to avoid overfitting. The best cut-off value based on three-months clinical-response was applied to progression-free survival (PFS) and overall survival (OS). Kaplan-Meier-curves for PFS and OS were produced. RESULTS: At pre-treatment, mRCCs displayed high frequency of NKp46+NKs, NKp30+NKs, KIR2DL1+NKs, KIR2DL2/DL3+NKs, and PD-1+NKs with reduced NK degranulation; as well as high frequency of Tregs, PD-1+Tregs, Helios+Tregs and ENTPD-1+Tregs. Responder patients (R), identified as a clinical response after three-months of treatment, presented at pre-treatment significantly low CD3+, high KIR2DL2/DL3+NKs, high PD-1+Tregs and high Helios+Tregs. Upon multivariate analysis, only KIR2DL2/DL3NKs and Helios+Tregs held as independent predictors of nivolumab responsiveness. The KIR2DL2/DL3+NKs >35.3% identified patients with longer OS while the Helios+Tregs >34.3% displayed significantly longer PFS. After 1-month of nivolumab, R patients showed low CD3+, high NKs, KIR2DL2/DL3+NKs and ICOS+Tregs. Among these subpopulations, CD3+ and KIR2DL2/DL3+NKs held as independent predictors of nivolumab efficacy. Low CD3+ (≤71%) significantly associated with longer PFS while high KIR2DL2/DL3+NKs (>23.3%) associated with both PFS and OS. CONCLUSIONS: Pre-treatment evaluation of Helios+Tregs/KIR2DL2/DL3+NKs and one-month post-treatment CD3+/ KIR2DL2/DL3+NKs will predict nivolumab response in mRCCs.