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<p>Neoadjuvant immunotherapies (NITs) have demonstrated clinical benefit in head and neck carcinoma and other cancers by enhancing T cell-mediated anti-tumor immunity. However, disease recurrence remains a major challenge in a significant proportion of patients. Characterization of T cell dynamics underlying NIT outcomes may lead to improved treatment strategies. Here, we identify baseline intratumoral T cell differentiation efficiency as a predictor of response to NIT. Clonal analysis of tumor-emergent T cells post-treatment revealed granzyme K (<i>GZMK)</i> expression within differentiated subsets as a marker of recent differentiation. Efficient pre-treatment differentiation of <i>GZMK</i><sup>+</sup> progenitor T cells toward activated effectors predicts increased treatment-induced tumor regression. Consistently, pre-treatment tumor-infiltrating T cell clones predominantly adopt either exhausted, tissue-resident memory-like, or peripherally enriched <i>GZMK</i><sup>+</sup> progenitor states, implicating impaired intratumoral differentiation in limited anti-tumor immunity at baseline. Together, our findings demonstrate that <i>GZMK</i><sup><i>+</i></sup> T cell profiles reflect baseline anti-tumor immunocompetence and offer a clinically actionable biomarker for predicting immunotherapy response. NCT04247282, ClinicalTrails.gov, registered 1/30/2020 and NCT03429036, ClinicalTrails.gov, registered 11/06/2020.</p>

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GZMK expression within activated intratumoral T-cell subsets reflects differentiation efficiency and predicts response to cancer immunotherapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月18日

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  • Cem M. Sievers,
  • Tian-Gen Chang,
  • Yvette Robbins,
  • Jay Friedman,
  • Marco Craveiro,
  • Xinping Yang,
  • Christopher Silvin,
  • Jason M. Redman,
  • Patrick Soon-Shiong,
  • Wiem Lassoued,
  • Martha Quezado,
  • Wojciech Mydlarz,
  • Nancy P. Judd,
  • Jeffrey Schlom,
  • James Gulley,
  • Eytan Ruppin,
  • Clint T. Allen

摘要

Neoadjuvant immunotherapies (NITs) have demonstrated clinical benefit in head and neck carcinoma and other cancers by enhancing T cell-mediated anti-tumor immunity. However, disease recurrence remains a major challenge in a significant proportion of patients. Characterization of T cell dynamics underlying NIT outcomes may lead to improved treatment strategies. Here, we identify baseline intratumoral T cell differentiation efficiency as a predictor of response to NIT. Clonal analysis of tumor-emergent T cells post-treatment revealed granzyme K (GZMK) expression within differentiated subsets as a marker of recent differentiation. Efficient pre-treatment differentiation of GZMK+ progenitor T cells toward activated effectors predicts increased treatment-induced tumor regression. Consistently, pre-treatment tumor-infiltrating T cell clones predominantly adopt either exhausted, tissue-resident memory-like, or peripherally enriched GZMK+ progenitor states, implicating impaired intratumoral differentiation in limited anti-tumor immunity at baseline. Together, our findings demonstrate that GZMK+ T cell profiles reflect baseline anti-tumor immunocompetence and offer a clinically actionable biomarker for predicting immunotherapy response. NCT04247282, ClinicalTrails.gov, registered 1/30/2020 and NCT03429036, ClinicalTrails.gov, registered 11/06/2020.