Distinct CD8+ T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

Men and women show striking yet unexplained discrepancies in incidence, clinical presentation, and therapeutic response across different types of infectious/autoimmune diseases and malignancies1,2. For instance, bladder cancer shows a 4-fold male-biased incidence that persists after adjustment for known risk factors3,4. Here, we utilize murine bladder cancer models to establish that male-biased tumor burden is driven by sex differences in endogenous T cell immunity. Notably, sex differences exist in early fate decisions by intratumoral CD8+ T cells following their activation. While female CD8+ T cells retain their effector function, male counterparts readily adopt a Tcf1lowTim3- progenitor state that becomes exhausted over tumor progression. Human cancers show an analogous male-biased frequency of exhausted CD8+ T cells. Mechanistically, we describe an opposing interplay between CD8+ T cell intrinsic androgen and type I interferon5,6 signaling in Tcf1/Tcf7 regulation and formation of the progenitor exhausted T cell subset. Consistent with female-biased interferon response7, testosterone-dependent stimulation of Tcf1/Tcf7 and resistance to interferon occurs to a greater magnitude in male CD8+ T cells. Male-biased predisposition for CD8+ T cell exhaustion suggests that spontaneous rejection of early immunogenic bladder tumors is less common in males and carries implications for therapeutic efficacy of immune checkpoint inhibitors8,9.