{"doi":"10.1101/2020.04.13.039735","title":"Distinct CD8 <sup>+</sup> T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome","abstract":"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 Tcf1 low Tim3 − 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 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 inhibitors 8,9 .","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":122693,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":242219,"name":"Dongjun Chung","orcid":"0000-0002-8072-5671","position":1,"is_corresponding":false},{"id":564436,"name":"Satoshi Kaneko","orcid":"0000-0001-8462-3245","position":2,"is_corresponding":false},{"id":270303,"name":"Anqi Li","orcid":"0000-0002-0367-0005","position":3,"is_corresponding":false},{"id":564437,"name":"Lei Zhou","orcid":"0000-0001-9291-8967","position":4,"is_corresponding":false},{"id":270305,"name":"Brian Riesenberg","orcid":"0000-0001-7358-3479","position":5,"is_corresponding":false},{"id":270304,"name":"No‐Joon Song","orcid":"0009-0002-0947-0597","position":6,"is_corresponding":false},{"id":564438,"name":"Debasish Sundi","orcid":"0000-0001-6980-4777","position":7,"is_corresponding":false},{"id":564439,"name":"Xue Li","orcid":"0000-0002-4530-1654","position":8,"is_corresponding":false},{"id":270306,"name":"Zihai Li","orcid":"0000-0003-4603-927X","position":9,"is_corresponding":false},{"id":564435,"name":"Hyunwoo Kwon","orcid":"0000-0002-8194-0672","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-18T23:14:55.385653Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}