Wijnen S C M A, Dimitriadis P, Reijers I L M, Menzies A M, Long G V, Wessels L F A, Blank C U
Department of Medical Oncology, Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.
Cancer Immunol Immunother. 2025 Jun 25;74(8):253. doi: 10.1007/s00262-025-04094-0.
Neoadjuvant combination therapy with anti-PD-1 and anti-CTLA4 agents has significantly improved long-term survival in patients with metastatic melanoma, yet not all patients respond to treatment. Responders often exhibit upregulated baseline inflammatory signatures; however, these markers capture only a single facet of the Cancer-Immunity Cycle-a comprehensive model describing the sequential steps required for effective anti-cancer immunity. To determine whether non-responsiveness to immunotherapy arises from single or multiple 'defective' steps, we analyzed in melanoma patients, treated with neoadjuvant immunotherapy, gene signatures representing each step of the cycle. Patients not achieving a major pathological response showed overall lower expression of these signatures. Among the 'immune-hot' patients, we identified a low response subgroup defective in one step ('homing-to-the-tumor,' involving CXCL9 and CXCL10), making this a promising target for improving their outcomes.
抗PD-1和抗CTLA4药物的新辅助联合疗法显著提高了转移性黑色素瘤患者的长期生存率，但并非所有患者都对治疗有反应。有反应者通常表现出基线炎症特征上调；然而，这些标志物仅捕捉到癌症-免疫循环的一个方面，癌症-免疫循环是一个描述有效抗癌免疫所需连续步骤的综合模型。为了确定免疫疗法无反应是由单个还是多个“缺陷”步骤引起的，我们分析了接受新辅助免疫疗法治疗的黑色素瘤患者中代表循环每个步骤的基因特征。未达到主要病理反应的患者总体上这些特征的表达较低。在“免疫活跃”患者中，我们确定了一个在一个步骤（“归巢至肿瘤”，涉及CXCL9和CXCL10）存在缺陷的低反应亚组，这使其成为改善其治疗结果的一个有希望的靶点。
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