Using major histocompatibility complex (MHC) II expression to predict antitumor response to CD4 + lymphocyte...

Immunotherapy targeting CD4 + FoxP3 + regulatory T cells (Tregs) through CD4 + lymphocyte depletion is being investigated as cancer treatment. This study examines the efficacy and limitations of CD4 depletion across various cancer models. We examined CD4 depletion in syngeneic mouse tumor models including B16 melanoma, Renca kidney cancer, and Hepa1-6 hepatocellular carcinoma. The study explored the relationship between MHC II expression and tumor growth, immune response, and survival. In mouse models, CD4 depletion suppressed B16 and Renca tumor growth but accelerated Hepa1-6 tumors. Hepa1-6 had high MHC II expression while the other two lines had low MHC II expression. Manipulation of MHC II expression in Hepa1-6 and Renca cell lines confirmed the mechanistic importance of MHC II in generating a CD4-based antitumor immune response. Analysis of the TCGA dataset supports the relevance of this mechanism in patients. In tumors with high MHC II and low MHC I expression, increased CD4 levels correlated with improved survival. CD4 depletion can suppress tumor growth or promote tumor growth, depending on tumor MHC expression status. MHC status may identify tumors where intratumor CD4 may be a better early-response marker than CD8.