WNT2 blockade augments antitumor immunity by attenuating myeloid-derived suppressor cells in colorectal cancer

Abstract

Colorectal cancer (CRC) ranks as one of the most common malignancies worldwide. Myeloid-derived suppressor cells (MDSCs) represent an immunosuppressive heterogeneous population of immature monocytes and granulocytes constituting a major obstacle for CRC therapy. Previous studies demonstrated that WNT2 is enriched in tumor microenvironment (TME), promoting CRC progression. However, the role of WNT2 in regulating MDSCs to facilitate CRC progression remains largely unexplored. Our analysis of The Cancer Genome Atlas (TCGA) database and blood samples from 50 primary and recurrent CRC patients revealed a positive correlation between WNT2 expression and MDSCs abundance. Treatment with recombinant WNT2 protein significantly enhanced the accumulation and immunosuppressive function of MDSCs in vitro. Conversely, anti-WNT2 monoclonal antibody remarkably reduced the percentage and functional activity of MDSCs in CRC tumor-bearing mice. Mechanistic analyses further demonstrated that WNT2 mediates MDSCs activities through the p38 MAPK/Akt pathway. Collectively, our findings not only highlight the pivotal role of WNT2 in CRC progression by enhancing MDSCs activities within the TME, but also provide evidence that WNT2 levels and MDSCs abundance in peripheral blood could serve as predictive biomarkers for early diagnosis and prognosis of CRC patients.