MHC-II antigen presentation on cancer cells improves CD4+ T cell immunity and vaccine efficacy

CD4+ T cells can be either protective or pathogenic in cancer [1-5], but how they interact with cancer cells to produce these effects remains poorly understood. Here, we developed a flexible autochthonous platform to introduce CD4+ T cell antigens in combination with CD8+ T cell antigens in a mouse lung cancer model. We found that tumor-specific CD4+ T cells potentiate CD8+ T cell control of tumor progression. Unlike previous studies emphasizing intratumoral interactions among dendritic cells, CD4+ T cells, and CD8+ T cells [4,5], we found that CD4+ T cell function and tumor control depend on direct antigen presentation by cancer cells via major histocompatibility complex class II (MHC-II). This direct interaction between cancer cells and CD4+ T cells led to increased immune infiltration, inflammatory remodeling, and sustained CD8+ T cell effector functions within tumors. Building on this, we demonstrate that tumor vaccination targeting both CD4+ and CD8+ T cell neoantigens significantly reduces tumor burden and requires cancer cell MHC-II presentation. These findings reveal an underappreciated mechanism of CD4+ T cell “help” and suggest a therapeutic approach targeting cancer cell presentation of MHC class II antigens.