{"doi":"10.1002/cam4.3739","title":"Bladder cancer cell‐intrinsic PD‐L1 signals promote mTOR and autophagy activation that can be inhibited to improve cytotoxic chemotherapy","abstract":"Tumor cell-intrinsic programmed death-ligand 1 (PD-L1) signals mediate immunopathologic effects in breast, colon, and ovarian cancers and in melanomas, but bladder cancer (BC) effects are unreported. We show here that BC cell-intrinsic PD-L1 signals in mouse MB49 and human RT4, UM-UC3, and UM-UC-14 BC cells regulate important pathologic pathways and processes, including effects not reported in other cancers. α-PD-L1 antibodies reduced BC cell proliferation in vitro, demonstrating direct signaling effects. BC cell-intrinsic PD-L1 promoted mammalian target of rapamycin complex 1 (mTORC1) signals in vitro and augmented in vivo immune-independent cell growth and metastatic cancer spread, similar to effects we reported in melanoma and ovarian cancer. BC cell-intrinsic PD-L1 signals also promoted basal and stress-induced autophagy, whereas these signals inhibited autophagy in melanoma and ovarian cancer cells. BC cell-intrinsic PD-L1 also mediated chemotherapy resistance to the commonly used BC chemotherapy agents cis-platinum and gemcitabine and to the mTORC1 inhibitor, rapamycin. Thus, BC cell-intrinsic PD-L1 signals regulate important virulence and treatment resistance pathways that suggest novel, actionable treatment targets meriting additional studies. As a proof-of-concept, we showed that the autophagy inhibitor chloroquine improved cis-platinum treatment efficacy in vivo, with greater efficacy in PD-L1 null versus PD-L1-replete BC.","journal":"Cancer Medicine","year":2021,"id":162436,"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":47,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":679702,"name":"Ryan M. Reyes","orcid":"0000-0002-9562-5809","position":1,"is_corresponding":false},{"id":679703,"name":"Erica Osta","orcid":"0000-0002-5264-5543","position":2,"is_corresponding":false},{"id":679704,"name":"Suresh Kari","orcid":"0000-0002-9927-4014","position":3,"is_corresponding":false},{"id":679705,"name":"Harshita B. Gupta","orcid":"0000-0003-1003-2658","position":4,"is_corresponding":false},{"id":680781,"name":"Álvaro Padrón","orcid":null,"position":5,"is_corresponding":false},{"id":680782,"name":"Anand Kornepati","orcid":null,"position":6,"is_corresponding":false},{"id":515345,"name":"Aravind Kancharla","orcid":"0000-0001-9095-7735","position":7,"is_corresponding":false},{"id":341852,"name":"Xiujie Sun","orcid":"0000-0003-3814-7406","position":8,"is_corresponding":false},{"id":409521,"name":"Yilun Deng","orcid":"0000-0002-7209-7855","position":9,"is_corresponding":false},{"id":341850,"name":"Bogang Wu","orcid":"0000-0003-1654-198X","position":10,"is_corresponding":false},{"id":275898,"name":"Ratna K. Vadlamudi","orcid":"0000-0003-2849-4076","position":11,"is_corresponding":false},{"id":334186,"name":"Rong Li","orcid":"0000-0002-6471-6580","position":12,"is_corresponding":false},{"id":679706,"name":"Robert S. Svatek","orcid":"0000-0002-0239-1338","position":13,"is_corresponding":false},{"id":341855,"name":"Tyler J. Curiel","orcid":"0000-0001-6962-9411","position":14,"is_corresponding":false},{"id":617656,"name":"Deyi Zhang","orcid":"0000-0002-1581-2357","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-18T23:45:05.641178Z","pmid":"33626233","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":[]}