Reduced tumor control in males can result from impaired CD4+ T-cell help through the CD40L–CD40 pathway

Sex-based differences in cancer incidence are incompletely understood, but potential roles for the immune system are beginning to emerge. CD4+ T cells play a central role in coordinating antitumor immunity. In addition to cytokine production, CD40L expression on CD4+ T cells provides necessary helper signaling to dendritic cells that is required for the priming of cytotoxic tumor-specific CD8+ T cells. Despite these critical functions, the impact of biological sex on the CD4+ T-cell response to cancer remains unknown. Here, we demonstrate that impaired immune-mediated tumor control in male mice compared to female mice is driven by disparate CD4+ T-cell responses in a mouse model of bladder cancer. We found that CD40L expression was reduced on CD4+ T cells isolated from males via a mechanism predominantly driven by cell-intrinsic androgen receptor signaling, resulting in decreased dendritic cell licensing through CD40 within tumor-draining lymph nodes. These deficits resulted in decreased helper CD4+ T-cell frequencies and impaired CD8+ T-cell function within the male tumor microenvironment which could be rescued by targeting the CD40L–CD40 axis. Our findings identify a novel mechanism of CD4+ T cell–based sex differences in the immune response to cancer that impairs tumor control.