Ubiquitin-activating enzyme mediates immune escape via suppressing interferon signaling

How cancer cells escape immune surveillance and resist immunotherapies remain to be elucidated. By screening candidate genes frequently amplified in cancer, we identified expression of ubiquitin-activating enzyme (UBA1) as being the most negatively correlated with signatures related to effector CD8+T cells. High expression of UBA1was strongly predictive of resistance to immune checkpoint blockade (ICB) and poor survival in ICB cohorts. In immunocompetent syngeneic models, but not in immunodeficient models, we found that overexpression ofUba1in cancer cells promoted tumor growth and reduced functional, intratumoral CD8+T cells. Conversely, depletion ofUba1impaired tumor progression, accompanied with increase of functional, intratumoral CD8+T cells. CD8+T cell depletion rescued tumor growth impairment mediated byUba1depletion. Additionally, a selective, small molecule inhibitor of UBA1, TAK-243, delayed tumor growth and augmented ICB in various syngeneic models, in a manner dependent on CD8+T cells. Intratumoral administration of TAK-243 and tumor rechallenge experiments revealed that TAK-243 treatment exhibited a remarkable abscopal effect and provided prolonged protection against cancer, accompanied with elevation of memory CD8+ T cells. Mechanistically, depletion or inactivation of UBA1 stabilized the short-lived interferon (IFN) pathway component, JAK1, upregulated both type-I and -II IFN signaling pathways, and resulted in elevation of key immune modulators, including CXCL9, CXCL10, and MHC-I. Taken together, our data supports that UBA1 mediates cancer immune escape via suppressing interferon signaling and suggests that targeting UBA1 may activate systemic cancer immunity.