Sexual Dimorphism in Cancer Immunity

Sex is a biological variable with significant influence on immune function (3). However, immunological mechanisms underlying sex-based incidence, clinical presentation and therapeutic response across various cancers arising in nonreproductive organs remain elusive (4). In the first aim of this dissertation, we provide evidence for sex differences in anti-tumor immunity in human cancer patients via the retrospective analysis of their peripheral blood specimens. For instance, we observed that platelet and neutrophil counts correlate with overall survival in male patients with head and neck squamous cell carcinoma (HNSCC). In contrast, only lymphocyte counts showed prognostic significance in female counterparts. Furthermore, computational analyses of HNSCC RNA-seq data from The Cancer Genome Atlas revealed that intratumoral T cell gene signature associated with increased survival more strikingly in females than in males. In the second aim, we characterize sexual dimorphism in T cell mediated anti-tumor immunity in the context of bladder cancer, which often displays high immunogenicity and shows a 3 to 4-fold higher incidence in men that cannot be statistically accounted for by social risk factors (5, 6). We report that bladder cancer male bias, as replicated by multiple murine models, is largely mediated by sex differences in T cell immunity. Flow cytometric and single cell RNA-seq analyses of CD8+ tumor-infiltrating leukocytes (TILs) identified a striking male bias in the formation of Tcf1lowTim3- progenitor cells (7) and in their transition to a hypofunctional Tcf1-Tim3+ exhausted state over tumor progression. Conversely, female CD8+ TILs retained their effector function. Human cancers showed an analogous male-biased frequency of exhausted CD8+ TILs. Mechanistically, we describe an opposing interplay between cell-intrinsic androgen and type I interferon signaling (8, 9) in Tcf1/Tcf7 regulation. Testosterone-induced Tcf1, an early molecular orchestrator of an exhaustion-associated transcriptional landscape (10) in male CD8+ T cells, shows more resistance to repression by female-biased type I interferon signaling (8). 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 cancer immunotherapy (11, 12)