Hyperexpression of pseudouridine synthases in tumors promotes immune evasion by regulating mRNA splicing
Description
Epigenetic plasticity is essential for tumor transformation, progression and immunotherapy responses. Despite pseudouridine is the first discovered and most abundant epitranscriptomic modification, little is known about its cellular functions. Here, we identified pseudouridine synthase (PUS) as a crucial factor for tumor immune evasion. Notably, aberrant hyperexpression of PUS in tumors inhibited T cell infiltration and function, and was positively correlated with tumor malignant progression as well as poor patient clinical outcomes, especially in TP53 mutation tumors. Importantly, PUS loss not only inhibited liver tumor progression in vivo, but also sensitized tumor cells to anti-PD1 therapy in the de novo MYC/Trp53-/- mouse liver cancer model. Furthermore, single cell RNA sequencing analysis revealed that PUS promoted tumor heterogeneity and diversity. Mechanistically, these tumor progression, heterogeneity and diversity-promoting effects of PUS were achieved by regulating mRNA splicing, which led to an immune microenvironment reprogramming and tumor aggressive phenotype. We further demonstrated that the functions of PUS1 in promoting liver tumor progression and immune evasion were dependent on its enzyme activity. Clinically, low PUS level showed a higher response rate and better clinical outcome to immune checkpoint blockade (ICB) therapies. Overall, our findings reveal that PUS functions as a crucial regulator of immune evasion, and inhibition of PUS may be a novel therapeutic strategy to enhance cancer response to immunotherapy by turning a cold tumor into a hot one.