{"doi":"10.1186/s12964-021-00810-2","title":"Endoplasmic reticulum stress promotes the release of exosomal PD-L1 from head and neck cancer cells and facilitates M2 macrophage polarization","abstract":"<jats:title>Abstract</jats:title><jats:sec>\n                <jats:title>Background</jats:title>\n                <jats:p>Endoplasmic reticulum (ER) stress has been found to foster the escape of cancer cells from immune surveillance and upregulate PD-L1 expression. However, the underlying mechanisms are unknown.</jats:p>\n              </jats:sec><jats:sec>\n                <jats:title>Methods</jats:title>\n                <jats:p>While analyzing the protein levels using immunofluorescence and Western blotting, the RNA levels were measured using qRT-PCR. Ten injection of exosomes into six-week-old nude mice was made through the tail vein once every other day in total.</jats:p>\n              </jats:sec><jats:sec>\n                <jats:title>Results</jats:title>\n                <jats:p>The expression of certain ER stress markers such as PERK (PKR-like endoplasmic reticulum kinase), ATF6 (activating transcription factor 6), and GRP78 (glucose-regulated protein 78), was found to be upregulated in the oral squamous cell carcinoma (OSCC) tissues and related to poor overall survival. There is a positive relationship between the extent of ER stress-related proteins and a cluster of PD-L1 expression and macrophage infiltration among the OSCC tissues. Further, incubation with exosomes derived from ER-stressed HN4 cells (Exo-ER) was found to upregulate PD-L1 extents in macrophages in vitro and in vivo, and macrophage polarization toward the M2 subtype was promoted by upregulating PD-L1.</jats:p>\n              </jats:sec><jats:sec>\n                <jats:title>Conclusions</jats:title>\n                <jats:p>ER stress causes OSCC cells to secrete exosomal PD-L1 and upregulates PD-L1 expression in macrophages to drive M2 macrophage polarization. The delineation of a new exosome-modulated mechanism was made for OSCC–macrophage crosstalk driving tumor development and to be examined for its therapeutic use.</jats:p>\n              </jats:sec><jats:sec>\n                <jats:title>Graphical abstract</jats:title>\n                <jats:p>Exosomal PD-L1 secreted by ER-stressed OSCC cells promoted M2 macrophage polarization. </jats:p>\n                \n              </jats:sec>","journal":"Cell Communication and Signaling","year":2022,"id":625399,"datarank":0.6394019815561974,"base_score":4.2626798770413155,"endowment":4.2626798770413155,"self_citation_contribution":0.6394019815561974,"citation_network_contribution":0.0,"self_endowment_contribution":0.6394019815561974,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":70,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1351166,"name":"Pengfei Jiao","orcid":null,"position":1,"is_corresponding":false},{"id":1056382,"name":"Zeyu Wang","orcid":"0000-0002-6343-0548","position":2,"is_corresponding":false},{"id":1617356,"name":"Mengqi Chen","orcid":null,"position":3,"is_corresponding":false},{"id":1617357,"name":"Hongming Du","orcid":null,"position":4,"is_corresponding":false},{"id":1183389,"name":"Liang Xu","orcid":"0000-0003-3889-927X","position":5,"is_corresponding":false},{"id":1617358,"name":"Juanyong Xu","orcid":null,"position":6,"is_corresponding":false},{"id":1617359,"name":"Youjin Dai","orcid":null,"position":7,"is_corresponding":false},{"id":1617360,"name":"Fu-gen Wu","orcid":null,"position":8,"is_corresponding":false},{"id":509642,"name":"Yaqin Zhang","orcid":"0000-0003-3436-4569","position":9,"is_corresponding":false},{"id":1617361,"name":"Heming Wu","orcid":"0000-0002-1876-9585","position":10,"is_corresponding":false},{"id":728504,"name":"Yi Yuan","orcid":"0000-0001-8828-990X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Endoplasmic reticulum stress promotes the release of exosomal PD-L1 from head and neck cancer cells and facilitates M2 macrophage polarization","abstract":"BACKGROUND: Endoplasmic reticulum (ER) stress has been found to foster the escape of cancer cells from immune surveillance and upregulate PD-L1 expression. However, the underlying mechanisms are unknown. METHODS: While analyzing the protein levels using immunofluorescence and Western blotting, the RNA levels were measured using qRT-PCR. Ten injection of exosomes into six-week-old nude mice was made through the tail vein once every other day in total. RESULTS: The expression of certain ER stress markers such as PERK (PKR-like endoplasmic reticulum kinase), ATF6 (activating transcription factor 6), and GRP78 (glucose-regulated protein 78), was found to be upregulated in the oral squamous cell carcinoma (OSCC) tissues and related to poor overall survival. There is a positive relationship between the extent of ER stress-related proteins and a cluster of PD-L1 expression and macrophage infiltration among the OSCC tissues. Further, incubation with exosomes derived from ER-stressed HN4 cells (Exo-ER) was found to upregulate PD-L1 extents in macrophages in vitro and in vivo, and macrophage polarization toward the M2 subtype was promoted by upregulating PD-L1. CONCLUSIONS: ER stress causes OSCC cells to secrete exosomal PD-L1 and upregulates PD-L1 expression in macrophages to drive M2 macrophage polarization. The delineation of a new exosome-modulated mechanism was made for OSCC-macrophage crosstalk driving tumor development and to be examined for its therapeutic use. Exosomal PD-L1 secreted by ER-stressed OSCC cells promoted M2 macrophage polarization. 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