Cell Communication Network factor 4 promotes tumor-induced immunosuppression in melanoma

Cell Communication Network factor 4 (CCN4/WISP1) is a matricellular protein secreted by cancer cells that promotes metastasis by inducing the epithelial-mesenchymal transition. While metastasis limits survival, limited anti-tumor immunity also associates with poor patient outcomes with recent work linking these two clinical correlates. Motivated by increased CCN4 correlating with dampened anti-tumor immunity in primary melanoma, we test for a direct causal link by knocking out CCN4 (CCN4 KO) in the B16F0 and YUMM1.7 mouse melanoma models. Tumor growth is reduced when CCN4 KO melanoma cells are implanted in immunocompetent but not in immunodeficient mice. Correspondingly, CD45⁺ tumor-infiltrating leukocytes are significantly increased in CCN4 KO tumors, with increased natural killer and CD8⁺ T cells and reduced myeloid-derived suppressor cells (MDSC). Among mechanisms linked to local immunosuppression, CCN4 suppresses IFN-gamma release by CD8⁺ T cells and enhances tumor secretion of MDSC-attracting chemokines like CCL2 and CXCL1. Finally, CCN4 KO potentiates the anti-tumor effect of immune checkpoint blockade (ICB) therapy. Overall, our results suggest that CCN4 promotes tumor-induced immunosuppression and is a potential target for therapeutic combinations with ICB.