Improving Immunotherapy Response by Targeting Uchl5

Head and neck squamous cell carcinoma claims 450,000 to 480,000 lives globally every year, and with 50,000 to 70,000 new diagnoses annually in the US alone, the search for effective immunotherapies has been of significant clinical relevance. In a newly-published article from Nature, researchers from UC San Diego have identified a new target: Uchl5, short for Ubiquitin C-terminal Hydrolase L5. The role of Ubiquitin C-terminal Hydrolase L5 is to cleave ubiquitin (regulatory protein tag) off of proteins, thus preventing protein degradation. In simple terms, ubiquitin tags mark proteins for degradation, and Uchl5 prevents the breakdown of proteins by getting rid of the ubiquitin tags.

The researchers performed a genome-wide CRISPR screen using a mouse model of head and neck squamous cell carcinoma (HNSCC), specifically utilizing the SCAR (Screening for Cancer-Associated Regulators) vector system. The screen compared tumor growth in immunodeficient mice versus immunocompetent mice treated with immune checkpoint blockade (ICB) therapies, allowing them to isolate genes specifically involved in immune evasion and response to immunotherapy. They took millions of cancer cells and used CRISPR to "knock out" (break) a different gene in each cell, and one of the genes they knocked out was the Uchl5 gene. When they sequenced the tumors at the end, they noticed that cells missing Uchl5 had successfully grown in the immunodeficient mice, but had disappeared in the immunotherapy-treated mice. This suggested that Uchl5 was protecting the tumor from immunotherapy. From this, researchers were able to identify Uchl5 as important for immune evasion. Overexpression of Uchl5 correlated with poor response to immunotherapy.

Uchl5 deficiency downregulates epithelial-mesenchymal transition (EMT) transcriptional programs and attenuates extracellular matrix (ECM) production, specifically reducing the accumulation of fibrotic tissue (stromal desmoplasia) that normally acts as a physical barrier to immune cells. In other words, the mechanism of action of Uchl5 is to reduce the presence and/or strength of the physical barrier to immune cells, decreasing the ability of immune cells to respond to threats to health.

The paper also highlights the importance of COL17A1 (Collagen Type XVII Alpha 1 Chain), a key downstream mediator that excludes immune cells from tumors after being upregulated by Uchl5. COL17A1 further decreases immune defenses against cancer.

In summary, loss of Uchl5 led to significant increases in CD8+ T cell infiltration into the tumor and improved sensitivity to immunotherapies. The authors suggest that targeting UCHL5 or modulating the ECM could be a viable strategy to overcome resistance in HNSCC patients who currently show modest responses to standard immunotherapies.