{"doi":"10.1172/jci.insight.129353","title":"Differential effects of PD-L1 versus PD-1 blockade on myeloid inflammation in human cancer","abstract":"BACKGROUNDPD-1 and PD-L1 have been studied interchangeably in the clinic as checkpoints to reinvigorate T cells in diverse tumor types. Data for biologic effects of checkpoint blockade in human premalignancy are limited.METHODSWe analyzed the immunologic effects of PD-L1 blockade in a clinical trial of atezolizumab in patients with asymptomatic multiple myeloma (AMM), a precursor to clinical malignancy. Genomic signatures of PD-L1 blockade in purified monocytes and T cells in vivo were also compared with those following PD-1 blockade in lung cancer patients. Effects of PD-L1 blockade on monocyte-derived DCs were analyzed to better understand its effects on myeloid antigen-presenting cells.RESULTSIn contrast to anti-PD-1 therapy, anti-PD-L1 therapy led to a distinct inflammatory signature in CD14+ monocytes and increase in myeloid-derived cytokines (e.g., IL-18) in vivo. Treatment of AMM patients with atezolizumab led to rapid activation and expansion of circulating myeloid cells, which persisted in the BM. Blockade of PD-L1 on purified monocyte-derived DCs led to rapid inflammasome activation and synergized with CD40L-driven DC maturation, leading to greater antigen-specific T cell expansion.CONCLUSIONThese data show that PD-L1 blockade leads to distinct systemic immunologic effects compared with PD-1 blockade in vivo in humans, particularly manifest as rapid myeloid activation. These findings also suggest an additional role for PD-L1 as a checkpoint for regulating inflammatory phenotype of myeloid cells and antigen presentation in DCs, which may be harnessed to improve PD-L1-based combination therapies.TRIAL REGISTRATIONNCT02784483.FUNDINGThis work is supported, in part, by funds from NIH/NCI (NCI CA197603, CA238471, and CA208328).","journal":"JCI Insight","year":2020,"id":60388,"datarank":2.203948063276494,"base_score":4.143134726391533,"endowment":4.143134726391533,"self_citation_contribution":0.62147020895873,"citation_network_contribution":1.5824778543177638,"self_endowment_contribution":0.62147020895873,"citer_contribution":1.5824778543177638,"corpus_percentile":null,"corpus_rank":null,"citation_count":62,"citer_count":47,"citers_with_citation_signal":45,"citers_with_endowment":45,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9608,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT02784483"]},"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":318417,"name":"Federica Costa","orcid":"0000-0002-1742-9212","position":1,"is_corresponding":false},{"id":318418,"name":"Rituparna Das","orcid":"0000-0002-6497-5240","position":2,"is_corresponding":false},{"id":318419,"name":"Alyssa Duffy","orcid":"0000-0003-2848-8661","position":3,"is_corresponding":false},{"id":228858,"name":"Mehmet Samur","orcid":"0000-0002-9978-5682","position":4,"is_corresponding":false},{"id":318420,"name":"Samuel S. McCachren","orcid":"0000-0002-3073-4924","position":5,"is_corresponding":false},{"id":1573,"name":"Scott Gettinger","orcid":"0000-0003-0886-6880","position":6,"is_corresponding":false},{"id":106676,"name":"Natalia Neparidze","orcid":"0000-0001-9038-077X","position":7,"is_corresponding":false},{"id":319465,"name":"Terri L. Parker","orcid":null,"position":8,"is_corresponding":false},{"id":319466,"name":"Jithendra Kini Bailur","orcid":null,"position":9,"is_corresponding":false},{"id":318421,"name":"Katherine E. Pendleton","orcid":"0000-0001-9761-7303","position":10,"is_corresponding":false},{"id":280169,"name":"Richa Bajpai","orcid":null,"position":11,"is_corresponding":false},{"id":318422,"name":"Lin Zhang","orcid":"0000-0002-3767-0249","position":12,"is_corresponding":false},{"id":254043,"name":"Mina L. 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