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

<p><strong><span>Purpose</span></strong><span>: T<span>o identify predictive factors of nivolumab sensitivity, peripheral blood NKs and Tregs were evaluated </span>in patients with metastatic renal cancer (mRCC) enrolled in the REVOLUTION trial.</span></p> <p><strong><span>Experimental design:</span></strong><span> 57 mRCCs being treated with nivolumab, as at least second-line of therapy (REV), and 62 healthy donors (HDs) were longitudinally evaluated (</span><span>0-1-3-6-12 months</span><span>) for</span><span> peripheral NKs and Tregs, phenotype and function. </span><span>Multivariable logistic regression were conducted to identify the independent predictors. The </span><span>.632+ internal cross-validation was used to avoid overfitting. </span><span>The best cut-off value </span><span>based on three-months clinical-response</span><span> was applied to </span><span>progression-free survival (PFS)</span><span> and </span><span>overall survival (OS)</span><span>. Kaplan-Meier curves for PFS and OS were produced.</span></p> <p><strong><span>Results:</span></strong><span> </span><span>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, </span>^{<span>PD-1+</span>}<span>Tregs,</span>^{<span> Helios+</span>}<span>Tregs and </span>^{<span>ENTPD-1+</span>}<span>Tregs</span><span>. Responder patients (R), identified as a clinical response after three-months of treatment,</span><span> presented at pre-treatment significantly low CD3⁺, high^KIR2DL2/DL3+</span><span>NKs</span><span>, 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 &gt;35.3% identified patients with longer OS while the ^Helios+Tregs &gt;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⁺(&le;71%) significantly associated with longer PFS while high ^KIR2DL2/DL3+NKs (&gt;23.3%) associated with both PFS and OS. </span></p> <p><strong><span>Conclusions:</span></strong><span> Pre-treatment evaluation of ^Helios+Tregs/^KIR2DL2/DL3+NKs and one-month post-treatment CD3⁺/^KIR2DL2/DL3+NKs will predict nivolumab response in mRCCs<span>.</span></span></p>