USP15 Facilitates Colorectal Cancer Immune Evasion through SMYD3/CCL2-Dependent Myeloid-Derived Suppressor Cell Recruitment.

Abstract

Colorectal cancer (CRC) creates a suppressive tumor immune microenvironment (TIME) which leads to tumor progression and resistance to immune checkpoint inhibitor (ICI) therapy. Ubiquitin-specific peptidase 15 (USP15) broadly regulates immune responses and immune cell differentiation, but its involvement in shaping the TIME of CRC remains unclear. This study demonstrated that USP15 is over-expressed in CRC and correlated with poor prognosis. Employing colon orthotopic and metastatic tumor models, we performed loss- and gain-of-function assays for USP15, and revealed that over-expression of USP15 promotes tumor progression by increasing the abundance of myeloid-derived suppressor cells (MDSCs) and decreasing the presence of CD8+T cells in the TME. Through in vitro co-culture models and rescue experiments, we observed that tumoral USP15 decreased T cell abundance by promoting MDSC recruitment rather than directly affecting T cells. Mechanistically, we found that USP15 deubiquitinated SMYD3, thereby activating H3K4me3-mediated transcription and release of CCL2, which subsequently recruited MDSCs. Treatment with a USP15 inhibitor improved the efficacy of programmed cell death protein-1 (PD-1) blockade in CRC models. In a cohort of CRC patients undergoing immunotherapy, we observed that those with high USP15 expression had a poor response to anti-PD-1 therapy. In summary, this research explored how USP15 facilitates the recruitment of MDSCs and identified it as a promising target for enhancing immunotherapy in CRC.