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

Cong Fu1,2,3, Robert Saddawi-Konefka4,5, Jordan M Chinai1,2,3

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts, USA.

Nature Communications
|September 29, 2025
PubMed

Insights

Researchers identified ubiquitin C-terminal hydrolase 5 (UCHL5) as a key driver of immune evasion in head and neck squamous cell carcinoma (HNSCC). Targeting UCHL5 may enhance immunotherapy response by reducing extracellular matrix production and epithelial-mesenchymal transition.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) presents a significant challenge due to modest immunotherapy efficacy.
  • Enhancing immune checkpoint blockade (ICB) response in HNSCC is a critical unmet need.

Purpose of the Study:

  • To identify novel immune evasion genes in HNSCC using an in vivo CRISPR screen.
  • To investigate the role of identified genes, particularly UCHL5, in regulating ICB response.

Main Methods:

  • Conducted an in vivo CRISPR screen in a mouse model of HNSCC.
  • Assessed the impact of UCHL5 loss on tumor immune microenvironment and ICB response.
  • Analyzed extracellular matrix (ECM) production and epithelial-mesenchymal transition (EMT) pathways.
  • Investigated the role of COL17A1 in UCHL5-mediated immune evasion.

Main Results:

  • Identified UCHL5 as a regulator of ICB response in HNSCC.
  • Loss of Uchl5 increased CD8+ T cell infiltration and improved ICB efficacy.
  • Uchl5 deficiency reduced ECM production and EMT, counteracting stromal desmoplasia.
  • Found that COL17A1 contributes to UCHL5-mediated immune evasion in HNSCC.

Conclusions:

  • UCHL5 plays an unappreciated role in promoting EMT and immune evasion in HNSCC.
  • Modulating ECM production presents a potential strategy to enhance immunotherapy outcomes in HNSCC.
  • Targeting UCHL5 could improve anti-PD1 therapy effectiveness in HNSCC patients.

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