{"doi":"10.1084/jem.20211631","title":"CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma","abstract":"The resistance of pancreatic ductal adenocarcinoma (PDAC) to immune checkpoint inhibitors (ICIs) is attributed to the immune-quiescent and -suppressive tumor microenvironment (TME). We recently found that CCR2 and CCR5 were induced in PDAC following treatment with anti-PD-1 antibody (αPD-1); thus, we examined PDAC vaccine or radiation therapy (RT) as T cell priming mechanisms together with BMS-687681, a dual antagonist of CCR2 and CCR5 (CCR2/5i), in combination with αPD-1 as new treatment strategies. Using PDAC mouse models, we demonstrated that RT followed by αPD-1 and prolonged treatment with CCR2/5i conferred better antitumor efficacy than other combination treatments tested. The combination of RT + αPD-1 + CCR2/5i enhanced intratumoral effector and memory T cell infiltration but suppressed regulatory T cell, M2-like tumor-associated macrophage, and myeloid-derived suppressive cell infiltration. RNA sequencing showed that CCR2/5i partially inhibited RT-induced TLR2/4 and RAGE signaling, leading to decreased expression of immunosuppressive cytokines including CCL2/CCL5, but increased expression of effector T cell chemokines such as CCL17/CCL22. This study thus supports the clinical development of CCR2/5i in combination with RT and ICIs for PDAC treatment.","journal":"The Journal of Experimental Medicine","year":2022,"id":236807,"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":65,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":470007,"name":"May Tun Saung","orcid":"0000-0002-0698-0092","position":1,"is_corresponding":false},{"id":308452,"name":"Keyu Li","orcid":"0000-0002-4547-4918","position":2,"is_corresponding":false},{"id":514095,"name":"Juan Fu","orcid":null,"position":3,"is_corresponding":false},{"id":470006,"name":"Kenji Fujiwara","orcid":"0000-0001-5900-9382","position":4,"is_corresponding":false},{"id":308454,"name":"Nan Niu","orcid":"0000-0002-2360-2384","position":5,"is_corresponding":false},{"id":470010,"name":"Stephen Muth","orcid":"0000-0001-9381-3921","position":6,"is_corresponding":false},{"id":857861,"name":"Jun-Ke Wang","orcid":"0000-0002-8605-3087","position":7,"is_corresponding":false},{"id":857862,"name":"Yao Xu","orcid":"0000-0003-2171-3731","position":8,"is_corresponding":false},{"id":738297,"name":"Noah Rozich","orcid":"0000-0002-7816-2275","position":9,"is_corresponding":false},{"id":851695,"name":"Haley Zlomke","orcid":"0000-0002-3544-6841","position":10,"is_corresponding":false},{"id":858444,"name":"Sophia Y. 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