Article Dans Une Revue Clinical Cancer Research Année : 2024

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

Sara Santagata
Anna Maria Trotta
Crescenzo d'Alterio
Maria Napolitano
Giuseppina Rea
Marilena Di Napoli
Luigi Portella
Caterina Ieranò
Giuseppe Guardascione
Elisabetta Coppola
Helen Boyle
Joan Carles
Sabrina Rossetti
Rosa Azzaro
Florinda Feroce
Sisto Perdonà
Mario Fordellone
Anna Maria Bello
Daniela Califano
Paolo Chiodini
Sandro Pignata
Stefania Scala

Résumé

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.

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hal-04675471 , version 1 (03-04-2025)

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Sara Santagata, Anna Maria Trotta, Crescenzo d'Alterio, Maria Napolitano, Giuseppina Rea, et al.. KIR2DL2/DL3+NKs and Helios+Tregs in peripheral blood predict nivolumab response in patients with metastatic renal cell cancer. Clinical Cancer Research, 2024, ⟨10.1158/1078-0432.CCR-24-0729⟩. ⟨hal-04675471⟩
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