IRE1α regulates macrophage polarization, PD-L1 expression, and tumor survival
In the tumor microenvironment, local immune dysregulation is driven in part by macrophages and dendritic cells that are polarized to a mixed proinflammatory/immune-suppressive phenotype. The unfolded protein response (UPR) is emerging as the possible origin of these events. Here we report that the i...
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| creator | Batista, Alyssa Rodvold, Jeffrey J Xian, Su Searles, Stephen C Lew, Alyssa Iwawaki, Takao Almanza, Gonzalo Waller, T Cameron Lin, Jonathan Jepsen, Kristen Carter, Hannah Zanetti, Maurizio |
| description | In the tumor microenvironment, local immune dysregulation is driven in part by macrophages and dendritic cells that are polarized to a mixed proinflammatory/immune-suppressive phenotype. The unfolded protein response (UPR) is emerging as the possible origin of these events. Here we report that the inositol-requiring enzyme 1 (IRE1α) branch of the UPR is directly involved in the polarization of macrophages in vitro and in vivo, including the up-regulation of interleukin 6 (IL-6), IL-23, Arginase1, as well as surface expression of CD86 and programmed death ligand 1 (PD-L1). Macrophages in which the IRE1α/X-box binding protein 1 (Xbp1) axis is blocked pharmacologically or deleted genetically have significantly reduced polarization and CD86 and PD-L1 expression, which was induced independent of IFNγ signaling, suggesting a novel mechanism in PD-L1 regulation in macrophages. Mice with IRE1α- but not Xbp1-deficient macrophages showed greater survival than controls when implanted with B16.F10 melanoma cells. Remarkably, we found a significant association between the IRE1α gene signature and CD274 gene expression in tumor-infiltrating macrophages in humans. RNA sequencing (RNASeq) analysis showed that bone marrow-derived macrophages with IRE1α deletion lose the integrity of the gene connectivity characteristic of regulated IRE1α-dependent decay (RIDD) and the ability to activate CD274 gene expression. Thus, the IRE1α/Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immune surveillance. |
| doi_str_mv | 10.1371/journal.pbio.3000687 |
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The unfolded protein response (UPR) is emerging as the possible origin of these events. Here we report that the inositol-requiring enzyme 1 (IRE1α) branch of the UPR is directly involved in the polarization of macrophages in vitro and in vivo, including the up-regulation of interleukin 6 (IL-6), IL-23, Arginase1, as well as surface expression of CD86 and programmed death ligand 1 (PD-L1). Macrophages in which the IRE1α/X-box binding protein 1 (Xbp1) axis is blocked pharmacologically or deleted genetically have significantly reduced polarization and CD86 and PD-L1 expression, which was induced independent of IFNγ signaling, suggesting a novel mechanism in PD-L1 regulation in macrophages. Mice with IRE1α- but not Xbp1-deficient macrophages showed greater survival than controls when implanted with B16.F10 melanoma cells. Remarkably, we found a significant association between the IRE1α gene signature and CD274 gene expression in tumor-infiltrating macrophages in humans. RNA sequencing (RNASeq) analysis showed that bone marrow-derived macrophages with IRE1α deletion lose the integrity of the gene connectivity characteristic of regulated IRE1α-dependent decay (RIDD) and the ability to activate CD274 gene expression. Thus, the IRE1α/Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immune surveillance.</description><identifier>ISSN: 1545-7885</identifier><identifier>ISSN: 1544-9173</identifier><identifier>EISSN: 1545-7885</identifier><identifier>DOI: 10.1371/journal.pbio.3000687</identifier><identifier>PMID: 32520957</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activating transcription factor 1 ; Animals ; Antigen presentation ; Apoptosis ; B7-H1 Antigen - metabolism ; Batista, Jeffrey ; Bioinformatics ; Biology ; Biology and Life Sciences ; Bone marrow ; Cancer ; CD11b Antigen - metabolism ; CD86 antigen ; Cell Line, Tumor ; Cell Polarity ; Cell Proliferation ; Cell Survival ; Cytomegalovirus ; Dendritic cells ; Endoribonucleases - metabolism ; Enzymes ; Gene deletion ; Gene expression ; Gene Expression Regulation, Neoplastic ; Gene sequencing ; Genotype & phenotype ; Homeostasis ; Humans ; Immunology ; Immunosurveillance ; Inflammation ; Inflammation - pathology ; Inositol ; Interleukin 23 ; Interleukin 6 ; Kinases ; Laboratories ; Linear Models ; Macrophages ; Macrophages - metabolism ; Medicine ; Medicine and Health Sciences ; Melanoma ; Mice, Inbred C57BL ; Mice, Knockout ; Myeloid Cells - metabolism ; Neoplasms - metabolism ; Neoplasms - pathology ; PD-L1 protein ; Phenotype ; Phenotypes ; Polarization ; Protein folding ; Protein Serine-Threonine Kinases - metabolism ; Proteins ; Research and analysis methods ; Ribonucleic acid ; RNA ; Sensors ; Surgical implants ; Survival ; Transcription factors ; Tumors ; Unfolded Protein Response ; X-Box Binding Protein 1 - metabolism ; γ-Interferon</subject><ispartof>PLoS biology, 2020-06, Vol.18 (6), p.e3000687-e3000687</ispartof><rights>2020 Batista et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Batista et al 2020 Batista et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-504ec2d2a1082e9b0c925b4f1c56edd845b045ef7b53df584deef5cb1846035a3</citedby><cites>FETCH-LOGICAL-c526t-504ec2d2a1082e9b0c925b4f1c56edd845b045ef7b53df584deef5cb1846035a3</cites><orcidid>0000-0001-8753-1979 ; 0000-0002-8295-876X ; 0000-0002-0313-6646 ; 0000-0001-6346-8776</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307794/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307794/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32520957$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Batista, Alyssa</creatorcontrib><creatorcontrib>Rodvold, Jeffrey J</creatorcontrib><creatorcontrib>Xian, Su</creatorcontrib><creatorcontrib>Searles, Stephen C</creatorcontrib><creatorcontrib>Lew, Alyssa</creatorcontrib><creatorcontrib>Iwawaki, Takao</creatorcontrib><creatorcontrib>Almanza, Gonzalo</creatorcontrib><creatorcontrib>Waller, T Cameron</creatorcontrib><creatorcontrib>Lin, Jonathan</creatorcontrib><creatorcontrib>Jepsen, Kristen</creatorcontrib><creatorcontrib>Carter, Hannah</creatorcontrib><creatorcontrib>Zanetti, Maurizio</creatorcontrib><title>IRE1α regulates macrophage polarization, PD-L1 expression, and tumor survival</title><title>PLoS biology</title><addtitle>PLoS Biol</addtitle><description>In the tumor microenvironment, local immune dysregulation is driven in part by macrophages and dendritic cells that are polarized to a mixed proinflammatory/immune-suppressive phenotype. The unfolded protein response (UPR) is emerging as the possible origin of these events. Here we report that the inositol-requiring enzyme 1 (IRE1α) branch of the UPR is directly involved in the polarization of macrophages in vitro and in vivo, including the up-regulation of interleukin 6 (IL-6), IL-23, Arginase1, as well as surface expression of CD86 and programmed death ligand 1 (PD-L1). Macrophages in which the IRE1α/X-box binding protein 1 (Xbp1) axis is blocked pharmacologically or deleted genetically have significantly reduced polarization and CD86 and PD-L1 expression, which was induced independent of IFNγ signaling, suggesting a novel mechanism in PD-L1 regulation in macrophages. Mice with IRE1α- but not Xbp1-deficient macrophages showed greater survival than controls when implanted with B16.F10 melanoma cells. Remarkably, we found a significant association between the IRE1α gene signature and CD274 gene expression in tumor-infiltrating macrophages in humans. RNA sequencing (RNASeq) analysis showed that bone marrow-derived macrophages with IRE1α deletion lose the integrity of the gene connectivity characteristic of regulated IRE1α-dependent decay (RIDD) and the ability to activate CD274 gene expression. Thus, the IRE1α/Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immune surveillance.</description><subject>Activating transcription factor 1</subject><subject>Animals</subject><subject>Antigen presentation</subject><subject>Apoptosis</subject><subject>B7-H1 Antigen - metabolism</subject><subject>Batista, Jeffrey</subject><subject>Bioinformatics</subject><subject>Biology</subject><subject>Biology and Life Sciences</subject><subject>Bone marrow</subject><subject>Cancer</subject><subject>CD11b Antigen - metabolism</subject><subject>CD86 antigen</subject><subject>Cell Line, Tumor</subject><subject>Cell Polarity</subject><subject>Cell Proliferation</subject><subject>Cell Survival</subject><subject>Cytomegalovirus</subject><subject>Dendritic cells</subject><subject>Endoribonucleases - metabolism</subject><subject>Enzymes</subject><subject>Gene deletion</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene sequencing</subject><subject>Genotype & phenotype</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Immunology</subject><subject>Immunosurveillance</subject><subject>Inflammation</subject><subject>Inflammation - pathology</subject><subject>Inositol</subject><subject>Interleukin 23</subject><subject>Interleukin 6</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Linear Models</subject><subject>Macrophages</subject><subject>Macrophages - metabolism</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Melanoma</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Myeloid Cells - metabolism</subject><subject>Neoplasms - metabolism</subject><subject>Neoplasms - pathology</subject><subject>PD-L1 protein</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>Polarization</subject><subject>Protein folding</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Proteins</subject><subject>Research and analysis methods</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Sensors</subject><subject>Surgical implants</subject><subject>Survival</subject><subject>Transcription factors</subject><subject>Tumors</subject><subject>Unfolded Protein Response</subject><subject>X-Box Binding Protein 1 - 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The unfolded protein response (UPR) is emerging as the possible origin of these events. Here we report that the inositol-requiring enzyme 1 (IRE1α) branch of the UPR is directly involved in the polarization of macrophages in vitro and in vivo, including the up-regulation of interleukin 6 (IL-6), IL-23, Arginase1, as well as surface expression of CD86 and programmed death ligand 1 (PD-L1). Macrophages in which the IRE1α/X-box binding protein 1 (Xbp1) axis is blocked pharmacologically or deleted genetically have significantly reduced polarization and CD86 and PD-L1 expression, which was induced independent of IFNγ signaling, suggesting a novel mechanism in PD-L1 regulation in macrophages. Mice with IRE1α- but not Xbp1-deficient macrophages showed greater survival than controls when implanted with B16.F10 melanoma cells. Remarkably, we found a significant association between the IRE1α gene signature and CD274 gene expression in tumor-infiltrating macrophages in humans. RNA sequencing (RNASeq) analysis showed that bone marrow-derived macrophages with IRE1α deletion lose the integrity of the gene connectivity characteristic of regulated IRE1α-dependent decay (RIDD) and the ability to activate CD274 gene expression. Thus, the IRE1α/Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immune surveillance.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>32520957</pmid><doi>10.1371/journal.pbio.3000687</doi><orcidid>https://orcid.org/0000-0001-8753-1979</orcidid><orcidid>https://orcid.org/0000-0002-8295-876X</orcidid><orcidid>https://orcid.org/0000-0002-0313-6646</orcidid><orcidid>https://orcid.org/0000-0001-6346-8776</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_2424466118 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Public Library of Science (PLoS) |
| subjects | Activating transcription factor 1 Animals Antigen presentation Apoptosis B7-H1 Antigen - metabolism Batista, Jeffrey Bioinformatics Biology Biology and Life Sciences Bone marrow Cancer CD11b Antigen - metabolism CD86 antigen Cell Line, Tumor Cell Polarity Cell Proliferation Cell Survival Cytomegalovirus Dendritic cells Endoribonucleases - metabolism Enzymes Gene deletion Gene expression Gene Expression Regulation, Neoplastic Gene sequencing Genotype & phenotype Homeostasis Humans Immunology Immunosurveillance Inflammation Inflammation - pathology Inositol Interleukin 23 Interleukin 6 Kinases Laboratories Linear Models Macrophages Macrophages - metabolism Medicine Medicine and Health Sciences Melanoma Mice, Inbred C57BL Mice, Knockout Myeloid Cells - metabolism Neoplasms - metabolism Neoplasms - pathology PD-L1 protein Phenotype Phenotypes Polarization Protein folding Protein Serine-Threonine Kinases - metabolism Proteins Research and analysis methods Ribonucleic acid RNA Sensors Surgical implants Survival Transcription factors Tumors Unfolded Protein Response X-Box Binding Protein 1 - metabolism γ-Interferon |
| title | IRE1α regulates macrophage polarization, PD-L1 expression, and tumor survival |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T20%3A27%3A53IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=IRE1%CE%B1%20regulates%20macrophage%20polarization,%20PD-L1%20expression,%20and%20tumor%20survival&rft.jtitle=PLoS%20biology&rft.au=Batista,%20Alyssa&rft.date=2020-06-01&rft.volume=18&rft.issue=6&rft.spage=e3000687&rft.epage=e3000687&rft.pages=e3000687-e3000687&rft.issn=1545-7885&rft.eissn=1545-7885&rft_id=info:doi/10.1371/journal.pbio.3000687&rft_dat=%3Cproquest_plos_%3E2424466118%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2424466118&rft_id=info:pmid/32520957&rft_doaj_id=oai_doaj_org_article_09d9905f93834110aacb9e0409ef3141&rfr_iscdi=true |