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

Author

Listed:
  • Cong Fu

    (Harvard Medical School
    Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Robert Saddawi-Konefka

    (University of California San Diego
    The University of Texas MD Anderson Cancer Center)

  • Jordan M. Chinai

    (Harvard Medical School
    Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Sarah Y. Kim

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Ashwin V. Kammula

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    University of Pennsylvania)

  • Jonathan J. Perera

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Stanford University School of Medicine)

  • Aiping Jiang

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Payal Tiwari

    (Harvard Medical School
    Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Erin N. Kistler

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Shiqi Tang

    (University of California San Diego
    Stanford University)

  • Sarah M. Luna

    (San Diego)

  • Kayla J. Colvin

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Juan Dubrot

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Cancer Center Clínica Universidad de Navarra (CCUN))

  • Seth Anderson

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    University of Pennsylvania)

  • Rachel A. Fetterman

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    UMass Chan Medical School)

  • Cun Lan Chuong

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Sarah K. Lane-Reticker

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Collins K. Cheruiyot

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Audrey J. Muscato

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Zahra Alipour

    (University of Pennsylvania
    Washington University School of Medicine)

  • 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
    Harvard Medical School)

  • Bradley E. Bernstein

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Ann Marie Egloff

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Kathleen B. Yates

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Rebecca D. Chernock

    (Washington University School of Medicine)

  • J. Silvio Gutkind

    (San Diego)

  • Ravindra Uppaluri

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Robert T. Manguso

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

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.

Suggested Citation

  • 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. Colv, 2025. "In vivo CRISPR screening in head and neck cancer reveals Uchl5 as an immunotherapy target," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63592-y
    DOI: 10.1038/s41467-025-63592-y
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    References listed on IDEAS

    as
    1. Robert T. Manguso & Hans W. Pope & Margaret D. Zimmer & Flavian D. Brown & Kathleen B. Yates & Brian C. Miller & Natalie B. Collins & Kevin Bi & Martin W. LaFleur & Vikram R. Juneja & Sarah A. Weiss &, 2017. "In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target," Nature, Nature, vol. 547(7664), pages 413-418, July.
    2. Jeffrey J. Ishizuka & Robert T. Manguso & Collins K. Cheruiyot & Kevin Bi & Arpit Panda & Arvin Iracheta-Vellve & Brian C. Miller & Peter P. Du & Kathleen B. Yates & Juan Dubrot & Ilana Buchumenski & , 2019. "Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade," Nature, Nature, vol. 565(7737), pages 43-48, January.
    3. Zhiyong Wang & Victoria H. Wu & Michael M. Allevato & Mara Gilardi & Yudou He & Juan Luis Callejas-Valera & Lynn Vitale-Cross & Daniel Martin & Panomwat Amornphimoltham & James Mcdermott & Bryan S. Yu, 2019. "Syngeneic animal models of tobacco-associated oral cancer reveal the activity of in situ anti-CTLA-4," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    4. Avishai Gavish & Michael Tyler & Alissa C. Greenwald & Rouven Hoefflin & Dor Simkin & Roi Tschernichovsky & Noam Galili Darnell & Einav Somech & Chaya Barbolin & Tomer Antman & Daniel Kovarsky & Thoma, 2023. "Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours," Nature, Nature, vol. 618(7965), pages 598-606, June.
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    Full references (including those not matched with items on IDEAS)

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