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.
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.
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.
Pre-treatment evaluation of Helios+Tregs/KIR2DL2/DL3+NKs and one-month post-treatment CD3+/ KIR2DL2/DL3+NKs will predict nivolumab response in mRCCs.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Aug 21 [Epub ahead of print]
Sara Santagata, Anna Maria Trotta, Crescenzo D'Alterio, Maria Napolitano, Giuseppina Rea, Marilena Di Napoli, Luigi Portella, Caterina Ieranò, Giuseppe Guardascione, Elisabetta Coppola, Christophe Caux, Bertrand Dubois, Helen J Boyle, Joan Carles, Sabrina Rossetti, Rosa Azzaro, Florinda Feroce, Sisto Perdonà, Mario Fordellone, Anna Maria Bello, Daniela Califano, Paolo Chiodini, Sandro Pignata, Stefania Scala
Istituto Nazionale Tumori-IRCCS-Fondazione, Italy., NCI Pascale, Napoli, Italy., Istituto Nazionale per lo Studio e la Cura dei Tumori, Napoli, Italy., NCI Pascale, Naples, Italy., Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Italy., Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, Italy., Istituto Nazionale Tumori - IRCCS -Fondazione G. Pascale, Naples, Italy., Centre de Recherche en Cancérologie de Lyon, Lyon, France., CRCL, UMR INSERM 1052, CNRS 5286, Lyon, France., Centre Léon Berard, LYON, France., Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Ist Nazionale dei Tumori, Naples, Italy., University of Campania "Luigi Vanvitelli", Naples, Italy., Istituto Nazionale Tumori -IRCCS- Fondazione G. Pascale- Napoli, Italia, Naples, Italy., Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Fondazione G Pascale, Napoli, Italy.