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<p>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.</p>

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Dissecting response to neoadjuvant immunotherapy-treated melanoma using cancer-immunity cycle-associated signatures

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月25日

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  • S. C. M. A. Wijnen,
  • P. Dimitriadis,
  • I. L. M. Reijers,
  • A. M. Menzies,
  • G. V. Long,
  • L. F. A. Wessels,
  • C. U. Blank

摘要

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.