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

• Published in: EMBO reports Vol. 23; no. 4; pp. e54127 - n/a
• Main Authors: Fernandez, Audry, Deng, Wentao, McLaughlin, Sarah L, Pirkey, Anika C, Rellick, Stephanie L, Razazan, Atefeh, Klinke, David J
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 05.04.2022; John Wiley and Sons Inc
• Subjects: Animal models; Animals; Autocrine signalling; CCN4/WISP1; CD45 antigen; CD8 antigen; CD8+ T cells; CD8-Positive T-Lymphocytes; Cell Communication; Cell interactions; Chemokines; Communication; Communications networks; Immune checkpoint; Immune Tolerance; Immunity; Immunocompetence; Immunodeficiency; Immunosuppression; Immunosuppression Therapy; Interferon; Leukocytes; Lymphocytes; Lymphocytes T; Melanoma; Melanoma - metabolism; Melanoma, Experimental; Mesenchyme; Metastases; Metastasis; Mice; Monocyte chemoattractant protein 1; myeloid‐derived suppressor cells; Natural killer cells; NK cells; Paracrine signalling; Proteins; Suppressor cells; Survival; Therapy; Tumor-infiltrating lymphocytes; Tumors; CCN4/WISP1; immunosuppression; CD8+ T cells; NK cells; myeloid-derived suppressor cells
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202154127

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. Synopsis Cell Communication Network factor 4, a secreted matricellular protein that promotes metastasis in melanoma, also suppresses anti‐tumor immunity via autocrine and paracrine mechanisms. CCN4 is a potential target in combination with immune checkpoint blockade therapy. Knockout of CCN4 reduces tumor growth and increases overall survival only in immunocompetent mice. CCN4 suppresses antitumor immunity by promoting CCL2 and CXCL1 secretion, leading to increased MDSC infiltration. CCN4 suppresses IFN‐γ release by CD8+ T cells through a paracrine mechanism resulting in lower CD45+ cell numbers. Knockout of CCN4 complements immune checkpoint blockade therapy. Cell Communication Network factor 4, a secreted matricellular protein that promotes metastasis in melanoma, also suppresses anti‐tumor immunity via autocrine and paracrine mechanisms. CCN4 is a potential target in combination with immune checkpoint blockade therapy.