Apr 14, 2020

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

BioRxiv : the Preprint Server for Biology
H. KwonZihai Li

Abstract

Men and women show striking yet unexplained discrepancies in incidence, clinical presentation, and therapeutic response across different types of infectious/autoimmune diseases and malignancies (1,2). For instance, bladder cancer shows a 4-fold male-biased incidence that persists after adjustment for known risk factors (3,4). 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 interferon (5,6) signaling in Tcf1/Tcf7 regulation and formation of the progenitor exhausted T cell subset. Consistent with female-biased interferon response (7), testosterone-dependent stimulation of Tcf1/Tcf7 and resistance to interferon occurs to a greater magnitude in male CD8+ T cells. Male-biased pre...Continue Reading

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