细胞通讯网络因子 4 促进黑色素瘤中肿瘤诱导的免疫抑制

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.