KIR2DL2/DL3+NKs and Helios+Tregs in Peripheral Blood Predict Nivolumab Response in Patients with Metastatic Renal Cell Cancer.

IF 10 1区医学 Q1 ONCOLOGY Clinical Cancer Research Pub Date : 2024-10-15 DOI:10.1158/1078-0432.CCR-24-0729

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

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Abstract

Purpose: To identify predictive factors of nivolumab sensitivity, peripheral blood NKs and regulatory T-cell (Treg) were evaluated in patients with metastatic renal cell carcinoma (mRCC) enrolled in the REVOLUTION trial.

Experimental design: Fifty-seven mRCCs being treated with nivolumab, as at least second-line of therapy, and 62 healthy donors were longitudinally evaluated (0-1-3-6-12 months) for peripheral NKs and Tregs, phenotype, and function. Multivariable logistic regression was conducted to identify the independent predictors. The 0.632+ internal cross-validation was used to avoid overfitting. The best cutoff value based on a 3-month clinical response was applied to progression-free survival (PFS) and overall survival (OS). Kaplan-Meier curves for PFS and OS were produced.

Results: At pretreatment, mRCCs displayed high frequency of NKp46+NKs, NKp30+NKs, KIR2DL1+NKs, KIR2DL2/DL3+NKs, and PD1+NKs with reduced NK degranulation as well as high frequency of Tregs, PD1+Tregs, Helios+Tregs, and ENTPD1+Tregs. Responder patients, identified as a clinical response after 3 months of treatment, presented at pretreatment significantly low CD3+, high KIR2DL2/DL3+NKs, high PD1+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, whereas the Helios+Tregs >34.3% displayed significantly longer PFS. After 1-month of nivolumab, responder 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%) was significantly associated with longer PFS, whereas high KIR2DL2/DL3+NKs (>23.3%) were associated with both PFS and OS.

Conclusions: Pretreatment evaluation of Helios+Tregs/KIR2DL2/DL3+NKs and 1-month posttreatment CD3+/ KIR2DL2/DL3+NKs will predict nivolumab response in mRCCs.

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外周血中的 KIR2DL2/DL3+NKs 和 Helios+Tregs 可预测转移性肾细胞癌患者对 nivolumab 的反应。

目的：为了确定尼伐单抗敏感性的预测因素，对参加REVOLUTION试验的转移性肾细胞癌（mRCC）患者的外周血NKs和Tregs进行了评估。实验设计：对至少作为二线疗法（REV）接受尼伐单抗治疗的57例mRCC患者和62例健康供体（HD）的外周血NKs和Tregs、表型和功能进行了纵向评估（0-1-3-6-12个月）。研究人员进行了多变量逻辑回归，以确定独立的预测因素。为避免过度拟合，采用了 .632+ 内部交叉验证。无进展生存期（PFS）和总生存期（OS）采用了基于三个月临床反应的最佳临界值。得出了无进展生存期和总生存期的 Kaplan-Meier 曲线：结果：治疗前，mRCCs显示出高频率的NKp46+NKs、NKp30+NKs、KIR2DL1+NKs、KIR2DL2/DL3+NKs和PD-1+NKs，NK脱颗粒减少；以及高频率的Tregs、PD-1+Tregs、Helios+Tregs和ENTPD-1+Tregs。治疗三个月后出现临床应答的应答患者（R）在治疗前表现出明显的低 CD3+、高 KIR2DL2/DL3+NKs、高 PD-1+Tregs 和高 Helios+Tregs。经过多变量分析，只有 KIR2DL2/DL3NKs 和 Helios+Tregs 是预测尼伐单抗反应性的独立指标。KIR2DL2/DL3+NKs>35.3%的患者OS时间更长，而Helios+Tregs>34.3%的患者PFS时间明显更长。使用 nivolumab 1 个月后，R 患者表现出低 CD3+、高 NKs、KIR2DL2/DL3+NKs 和 ICOS+Tregs。在这些亚群中，CD3+和KIR2DL2/DL3+NKs是预测尼伐单抗疗效的独立指标。低CD3+（≤71%）与较长的PFS显著相关，而高KIR2DL2/DL3+NKs（>23.3%）与PFS和OS相关：结论：治疗前对Helios+Tregs/KIR2DL2/DL3+NKs的评估以及治疗后一个月对CD3+/ KIR2DL2/DL3+NKs的评估可预测尼伐单抗对mRCC的反应。

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来源期刊

Clinical Cancer Research 医学-肿瘤学

CiteScore

20.10

自引率

1.70%

发文量

1207

审稿时长

2.1 months

期刊介绍： Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.