In vivo CRISPR screening in head and neck cancer reveals Uchl5 as an immunotherapy target
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<sup>+</sup> 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.
Authors
- Robert Saddawi‐Konefka (ORCID: https://orcid.org/0000-0002-9936-1695)
- Cong Fu (ORCID: https://orcid.org/0009-0009-2204-6441)
- Jordan M. Chinai (ORCID: https://orcid.org/0000-0002-3236-498X)
- Collins Cheruiyot (ORCID: https://orcid.org/0000-0003-1832-3329)
- Rebecca D. Chernock (ORCID: https://orcid.org/0000-0001-6253-0478)
- Ann Marie Egloff (ORCID: https://orcid.org/0000-0002-1182-2793)
- Jonathan Perera (ORCID: https://orcid.org/0000-0003-3224-6075)
- Ravindra Uppaluri (ORCID: https://orcid.org/0000-0001-5988-6828)
- Aiping Jiang (ORCID: https://orcid.org/0000-0002-8389-2950)
- Payal Tiwari
- Juan Dubrot (ORCID: https://orcid.org/0000-0002-8093-2208)
- Cun Lan Chuong
- Zahra Alipour
- B Bernstein (ORCID: https://orcid.org/0000-0002-5726-6278)
- Seth Anderson (ORCID: https://orcid.org/0000-0003-2419-0585)
- Ashwin V. Kammula (ORCID: https://orcid.org/0000-0001-5284-721X)
- Douglas R. Adkins (ORCID: https://orcid.org/0000-0003-3207-8227)
- Sarah Kate Lane-Reticker (ORCID: https://orcid.org/0000-0001-7267-9882)
- Kathleen B. Yates (ORCID: https://orcid.org/0000-0002-7383-5573)
- Kayla J. Colvin
- Audrey J. Muscato (ORCID: https://orcid.org/0000-0003-2009-6313)
- Robert T. Manguso (ORCID: https://orcid.org/0000-0003-1336-413X)
- Sarah Kim (ORCID: https://orcid.org/0000-0003-2290-6025)
- Shiqi Tang
- Gabriel K. Griffin (ORCID: https://orcid.org/0000-0002-4042-6757)
- Sarah M. Luna
- J. Silvio Gutkind
- Rachel A. Fetterman
- Erin N. Kistler
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- University of Massachusetts Chan Medical School (US)
- Washington University in St. Louis (US)
- University of California San Diego (US)
- Massachusetts General Hospital (US)
- Jewish Hospital (US)
- Dana-Farber Cancer Institute (US)
- Clinica Universidad de Navarra (ES)
- Center for Cancer Research (US)
- University of Pennsylvania (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-29
- DOI
- https://doi.org/10.1038/s41467-025-63592-y
- Citations
- 1
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Broad Institute
- National Cancer Institute
- National Institute of Dental and Craniofacial Research
- Moonshot Research and Development Program
- Cancer Moonshot