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

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 () and Robert T. Manguso ()
Additional contact information
Cong Fu: Harvard Medical School
Robert Saddawi-Konefka: University of California San Diego
Jordan M. Chinai: Harvard Medical School
Sarah Y. Kim: Broad Institute of MIT and Harvard
Ashwin V. Kammula: Broad Institute of MIT and Harvard
Jonathan J. Perera: Broad Institute of MIT and Harvard
Aiping Jiang: Broad Institute of MIT and Harvard
Payal Tiwari: Harvard Medical School
Erin N. Kistler: Broad Institute of MIT and Harvard
Shiqi Tang: University of California San Diego
Sarah M. Luna: San Diego
Kayla J. Colvin: Broad Institute of MIT and Harvard
Juan Dubrot: Broad Institute of MIT and Harvard
Seth Anderson: Broad Institute of MIT and Harvard
Rachel A. Fetterman: Broad Institute of MIT and Harvard
Cun Lan Chuong: Broad Institute of MIT and Harvard
Sarah K. Lane-Reticker: Broad Institute of MIT and Harvard
Collins K. Cheruiyot: Broad Institute of MIT and Harvard
Audrey J. Muscato: Broad Institute of MIT and Harvard
Zahra Alipour: University of Pennsylvania
Douglas R. Adkins: Washington University School of Medicine, Robert Ebert and Greg Stubblefield Head and Neck Tumor Center, Alvin J. Siteman Cancer Center, and Barnes Jewish Hospital
Gabriel K. Griffin: Broad Institute of MIT and Harvard
Bradley E. Bernstein: Broad Institute of MIT and Harvard
Ann Marie Egloff: Harvard Medical School
Kathleen B. Yates: Broad Institute of MIT and Harvard
Rebecca D. Chernock: Washington University School of Medicine
J. Silvio Gutkind: San Diego
Ravindra Uppaluri: Harvard Medical School
Robert T. Manguso: Broad Institute of MIT and Harvard

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63592-y

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