Impaired CD4+ T cell help through the CD40L-CD40 pathway contributes to reduced tumor control in males

Abstract 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 organizing antitumor immunity. In addition to cytokine production, CD40L expression on CD4⁺ T cell 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 compared to female mice is driven by disparate helper CD4⁺ T cell responses between the sexes. We find that CD40L expression is reduced on CD4⁺ T cells isolated from males via a mechanism predominantly driven by sex hormones, resulting in decreased CD40 signaling in dendritic cells 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. *Stephen T. Ferris & Elise Alspach are co-senior authors.