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<p>Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a significant unmet need for enhancing immunotherapy response given current modest efficacy. Here, we perform an in vivo CRISPR screen in an HNSCC mouse model to identify immune evasion genes. We identify several regulators of immune checkpoint blockade (ICB) response, including the ubiquitin C-terminal hydrolase 5 (UCHL5). Loss of <i>Uchl5</i> in tumors increases CD8<sup>+</sup> T cell infiltration and improved ICB responses. <i>Uchl5</i> deficiency attenuates extracellular matrix (ECM) production and epithelial-mesenchymal-transition (EMT) transcriptional programs, which contribute to stromal desmoplasia, a histologic finding we describe as associated with reduced anti-PD1 response in human HNSCCs. COL17A1, a collagen highly and specifically expressed in HNSCC, mediates in part <i>Uchl5</i>-mediated immune evasion. Our findings suggest an unappreciated role for UCHL5 in promoting EMT in HNSCC and highlight ECM modulation as a strategy to improve immunotherapy responses.</p>

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In vivo CRISPR screening in head and neck cancer reveals Uchl5 as an immunotherapy target

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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  • Cong Fu,
  • Robert Saddawi-Konefka,
  • Jordan M. Chinai,
  • Sarah Y. Kim,
  • Ashwin V. Kammula,
  • Jonathan J. Perera,
  • Aiping Jiang,
  • Payal Tiwari,
  • Erin N. Kistler,
  • Shiqi Tang,
  • Sarah M. Luna,
  • Kayla J. Colvin,
  • Juan Dubrot,
  • Seth Anderson,
  • Rachel A. Fetterman,
  • Cun Lan Chuong,
  • Sarah K. Lane-Reticker,
  • Collins K. Cheruiyot,
  • Audrey J. Muscato,
  • Zahra Alipour,
  • Douglas R. Adkins,
  • Gabriel K. Griffin,
  • Bradley E. Bernstein,
  • Ann Marie Egloff,
  • Kathleen B. Yates,
  • Rebecca D. Chernock,
  • J. Silvio Gutkind,
  • Ravindra Uppaluri,
  • Robert T. Manguso

摘要

Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a significant unmet need for enhancing immunotherapy response given current modest efficacy. Here, we perform an in vivo CRISPR screen in an HNSCC mouse model to identify immune evasion genes. We identify several regulators of immune checkpoint blockade (ICB) response, including the ubiquitin C-terminal hydrolase 5 (UCHL5). Loss of Uchl5 in tumors increases CD8+ T cell infiltration and improved ICB responses. Uchl5 deficiency attenuates extracellular matrix (ECM) production and epithelial-mesenchymal-transition (EMT) transcriptional programs, which contribute to stromal desmoplasia, a histologic finding we describe as associated with reduced anti-PD1 response in human HNSCCs. COL17A1, a collagen highly and specifically expressed in HNSCC, mediates in part Uchl5-mediated immune evasion. Our findings suggest an unappreciated role for UCHL5 in promoting EMT in HNSCC and highlight ECM modulation as a strategy to improve immunotherapy responses.