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

Area of Science:

• Immunology
• Oncology
• Cancer Biology

Background:

• Metastasis and suppressed anti-tumor immunity are linked to poor patient outcomes.
• Cell Communication Network factor 4 (CCN4/WISP1) is secreted by cancer cells and promotes metastasis.
• Increased CCN4 correlates with dampened anti-tumor immunity in melanoma.

Purpose of the Study:

• To investigate the causal link between CCN4 and suppressed anti-tumor immunity in melanoma.
• To determine if CCN4 knockout (KO) affects tumor growth and immune infiltration.
• To explore CCN4's role in immune evasion and its potential as a therapeutic target.

Main Methods:

• Utilized B16F0 and YUMM1.7 mouse melanoma models with CCN4 knockout.
• Implanted CCN4 KO and wild-type melanoma cells into immunocompetent and immunodeficient mice.
• Analyzed tumor-infiltrating leukocytes (TILs), including natural killer (NK) cells, CD8+ T cells, and myeloid-derived suppressor cells (MDSCs).
• Assessed cytokine and chemokine profiles (IFN-gamma, CCL2, CXCL1) and response to immune checkpoint blockade (ICB) therapy.

Main Results:

• CCN4 KO melanoma showed reduced tumor growth in immunocompetent but not immunodeficient mice.
• CCN4 KO tumors exhibited increased CD45+ TILs, including higher NK and CD8+ T cell counts, and reduced MDSCs.
• CCN4 was found to suppress CD8+ T cell IFN-gamma release and enhance MDSC-attracting chemokine secretion (CCL2, CXCL1).
• CCN4 KO significantly potentiated the anti-tumor efficacy of ICB therapy.

Conclusions:

• CCN4 actively promotes tumor-induced immunosuppression by impairing T cell function and recruiting suppressive myeloid cells.
• Targeting CCN4 may enhance anti-tumor immunity and improve responses to immunotherapy, particularly ICB.
• CCN4 represents a promising therapeutic target for combination strategies in melanoma treatment.