Soluble CD27 differentially predicts resistance to anti-PD1 alone but not with anti-CTLA-4 in melanoma.

IF 9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EMBO Molecular Medicine Pub Date : 2025-03-27 DOI:10.1038/s44321-025-00203-9

Ikuan Sam, Nadine Benhamouda, Lucie Biard, Laetitia Da Meda, Kristell Desseaux, Barouyr Baroudjan, Ines Nakouri, Marion Renaud, Aurélie Sadoux, Marina Alkatrib, Jean-François Deleuze, Maxime Battistella, Yimin Shen, Matthieu Resche-Rigon, Samia Mourah, Celeste Lebbe, Eric Tartour

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引用次数: 0

Abstract

Metastatic melanoma can be treated with anti-PD-1 monotherapy or in combination with anti-CTLA-4 or anti-Lag3. However, combination therapy is associated with a high risk of toxicity. Recently, we reported that high plasma soluble CD27 (sCD27) levels reflect the intratumoral interaction of CD70-CD27 and dysfunctional T cells in the tumor microenvironment of renal cell carcinoma. In this study, we first characterized the intratumoral expression of CD70 and CD27 in melanoma tumors and their interaction in vivo. We then reported a significant association between baseline sCD27 and anti-PD-1 resistance as assessed by progression-free survival, overall survival, or 12-month complete response in two prospective cohorts of melanoma patients. Multivariate analysis confirmed that sCD27 was independently associated with clinical outcomes. Notably, sCD27 did not predict clinical response to combination therapy in either cohort. This differential predictive value of sCD27 for the two therapeutic options was later confirmed by propensity score analysis. Our results suggest that high plasma sCD27 levels predict poorer efficacy of anti-PD1 monotherapy in metastatic melanoma, justifying therapeutic escalation with a combination of anti-PD1 and anti-CTLA-4.

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转移性黑色素瘤可采用抗PD-1单药治疗，也可与抗CTLA-4或抗Lag3联合治疗。然而，联合疗法具有较高的毒性风险。最近，我们报道了高血浆可溶性 CD27（sCD27）水平反映了肾细胞癌肿瘤微环境中 CD70-CD27 和功能失调 T 细胞的瘤内相互作用。在这项研究中，我们首先描述了黑色素瘤肿瘤中 CD70 和 CD27 的瘤内表达及其在体内的相互作用。然后，我们报告了在两个前瞻性黑色素瘤患者队列中，基线 sCD27 与抗 PD-1 抗药性之间存在明显的关联（以无进展生存期、总生存期或 12 个月完全应答来评估）。多变量分析证实，sCD27与临床结果有独立关联。值得注意的是，在两个队列中，sCD27 都不能预测联合疗法的临床反应。后来，倾向评分分析证实了 sCD27 对两种治疗方案的不同预测价值。我们的研究结果表明，高血浆sCD27水平预示着抗PD1单药治疗转移性黑色素瘤的疗效较差，因此有理由升级抗PD1和抗CTLA-4联合疗法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Molecular Medicine 医学-医学：研究与实验

CiteScore

17.70

自引率

0.90%

发文量

105

审稿时长

4-8 weeks

期刊介绍： EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)