{"doi":"10.1136/jitc-2022-004871","title":"Pharmacological tumor PDL1 depletion with chlorambucil treats ovarian cancer and melanoma: improves antitumor immunity and renders anti-PDL1-resistant tumors anti-PDL1-sensitive through NK cell effects","abstract":"BACKGROUND: Tumor intracellular programmed cell death ligand-1 (PDL1) mediates pathologic signals that regulate clinical treatment responses distinctly from surface-expressed PDL1 targeted by αPDL1 immune checkpoint blockade antibodies. METHODS: We performed a drug screen for tumor cell PDL1 depleting drugs that identified Food and Drug Administration (FDA)-approved chlorambucil and also 9-[2-(phosphonomethoxy)ethyl] guanine. We used in vitro and in vivo assays to evaluate treatment and signaling effects of pharmacological tumor PDL1 depletion focused on chlorambucil as FDA approved, alone or plus αPDL1. RESULTS: PDL1-expressing mouse and human ovarian cancer lines and mouse melanoma were more sensitive to chlorambucil-mediated proliferation inhibition in vitro versus corresponding genetically PDL1-depleted lines. Orthotopic peritoneal PDL1-expressing ID8agg ovarian cancer and subcutaneous B16 melanoma tumors were more chlorambucil-sensitive in vivo versus corresponding genetically PDL1-depleted tumors. Chlorambucil enhanced αPDL1 efficacy in tumors otherwise αPDL1-refractory, and improved antitumor immunity and treatment efficacy in a natural killer cell-dependent manner alone and plus αPDL1. Chlorambucil-mediated PDL1 depletion was relatively tumor-cell selective in vivo, and treatment efficacy was preserved in PDL1KO hosts, demonstrating tumor PDL1-specific treatment effects. Chlorambucil induced PDL1-dependent immunogenic tumor cell death which could help explain immune contributions. Chlorambucil-mediated PDL1 reduction mechanisms were tumor cell-type-specific and involved transcriptional or post-translational mechanisms, including promoting PDL1 ubiquitination through the GSK3β/β-TRCP pathway. Chlorambucil-mediated tumor cell PDL1 depletion also phenocopied genetic PDL1 depletion in reducing tumor cell mTORC1 activation and tumor initiating cell content, and in augmenting autophagy, suggesting additional treatment potential. CONCLUSIONS: Pharmacological tumor PDL1 depletion with chlorambucil targets tumor-intrinsic PDL1 signaling that mediates treatment resistance, especially in αPDL1-resistant tumors, generates PDL1-dependent tumor immunogenicity and inhibits tumor growth in immune-dependent and independent manners. It could improve treatment efficacy of selected agents in otherwise treatment-refractory, including αPDL1-refractory cancers, and is rapidly clinically translatable.","journal":"Journal for ImmunoTherapy of Cancer","year":2023,"id":345648,"datarank":0.38474240361923057,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.0,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9684,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":680781,"name":"Álvaro Padrón","orcid":null,"position":1,"is_corresponding":false},{"id":409521,"name":"Yilun Deng","orcid":"0000-0002-7209-7855","position":2,"is_corresponding":false},{"id":856174,"name":"Yiji Liao","orcid":"0000-0002-0849-4573","position":3,"is_corresponding":false},{"id":1086087,"name":"Clare J Murray","orcid":null,"position":4,"is_corresponding":false},{"id":856938,"name":"Carlos Ontiveros","orcid":null,"position":5,"is_corresponding":false},{"id":679704,"name":"Suresh Kari","orcid":"0000-0002-9927-4014","position":6,"is_corresponding":false},{"id":515345,"name":"Aravind Kancharla","orcid":"0000-0001-9095-7735","position":7,"is_corresponding":false},{"id":680782,"name":"Anand Kornepati","orcid":null,"position":8,"is_corresponding":false},{"id":716374,"name":"Myrna Garcia","orcid":null,"position":9,"is_corresponding":false},{"id":679702,"name":"Ryan M. Reyes","orcid":"0000-0002-9562-5809","position":10,"is_corresponding":false},{"id":679705,"name":"Harshita B. Gupta","orcid":"0000-0003-1003-2658","position":11,"is_corresponding":false},{"id":242941,"name":"José R. Conejo-García","orcid":"0000-0001-6431-4074","position":12,"is_corresponding":false},{"id":341855,"name":"Tyler J. 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