In vivo CRISPR screens in Head and Neck Cancer reveal that Uchl5 modulates extracellular matrix deposition to promote immune evasion [in vitro]

Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a high unmet need for enhancing immunotherapy given current modest responses. Here, we performed an in vivo CRISPR screen in a HNSCC mouse model to identify immune evasion genes. We identified several epigenetic regulators of immune checkpoint blockade (ICB) response, including the ubiquitin C-terminal hydrolase 5 (UCHL5). Loss of Uchl5 in tumors increased CD8+ T cell infiltration and improved ICB responses. Uchl5 deficiency reduced extracellular matrix (ECM) production and epithelial-mesenchymal-transition (EMT) transcriptional signatures, which contribute to stromal desmoplasia, a histologic finding associated with reduced anti-PD1 response in human HNSCCs. We identified a functional role for COL17A1, a collagen highly and specifically expressed in HNSCC, in 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.