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Article: Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1

TitleReactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1
Authors
KeywordsReactive oxygen species
Immune suppression
Programmed death ligand-1
Macrophages
Chemotherapy
Issue Date2019
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2019, v. 116, n. 10, p. 4326-4335 How to Cite?
AbstractThe combination of immune checkpoint blockade with chemotherapy is currently under investigation as a promising strategy for the treatment of triple negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) are the most prominent component of the breast cancer microenvironment because they influence tumor progression and the response to therapies. Here we show that macrophages acquire an immunosuppressive phenotype and increase the expression of programmed death ligand-1 (PD-L1) when treated with reactive oxygen species (ROS) inducers such as the glutathione synthesis inhibitor, buthionine sulphoximine (BSO), and paclitaxel. Mechanistically, these agents cause accumulation of ROS that in turn activate NF-κB signaling to promote PD-L1 transcription and the release of immunosuppressive chemokines. Systemic in vivo administration of paclitaxel promotes PD-L1 accumulation on the surface of TAMS in a mouse model of TNBC, consistent with in vitro results. Combinatorial treatment with paclitaxel and an anti-mouse PD-L1 blocking antibody significantly improved the therapeutic efficacy of paclitaxel by reducing tumor burden and increasing the number of tumor-associated cytotoxic T cells. Our results provide a strong rationale for the use of anti–PD-L1 blockade in the treatment of TNBC patients. Furthermore, interrogation of chemotherapy-induced PD-L1 expression in TAMs is warranted to define appropriate patient selection in the use of PD-L1 blockade.
Persistent Identifierhttp://hdl.handle.net/10722/292107
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 3.737
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorRoux, Cecilia-
dc.contributor.authorJafari, Soode Moghadas-
dc.contributor.authorShinde, Rahul-
dc.contributor.authorDuncan, Gordon-
dc.contributor.authorCescon, David W.-
dc.contributor.authorSilvester, Jennifer-
dc.contributor.authorChu, Mandy F.-
dc.contributor.authorHodgson, Kelsey-
dc.contributor.authorBerger, Thorsten-
dc.contributor.authorWakeham, Andrew-
dc.contributor.authorPalomero, Luis-
dc.contributor.authorGarcia-Valero, Mar-
dc.contributor.authorPujana, Miguel A.-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorMcGaha, Tracy L.-
dc.contributor.authorCappello, Paola-
dc.contributor.authorGorrini, Chiara-
dc.date.accessioned2020-11-17T14:55:47Z-
dc.date.available2020-11-17T14:55:47Z-
dc.date.issued2019-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2019, v. 116, n. 10, p. 4326-4335-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/292107-
dc.description.abstractThe combination of immune checkpoint blockade with chemotherapy is currently under investigation as a promising strategy for the treatment of triple negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) are the most prominent component of the breast cancer microenvironment because they influence tumor progression and the response to therapies. Here we show that macrophages acquire an immunosuppressive phenotype and increase the expression of programmed death ligand-1 (PD-L1) when treated with reactive oxygen species (ROS) inducers such as the glutathione synthesis inhibitor, buthionine sulphoximine (BSO), and paclitaxel. Mechanistically, these agents cause accumulation of ROS that in turn activate NF-κB signaling to promote PD-L1 transcription and the release of immunosuppressive chemokines. Systemic in vivo administration of paclitaxel promotes PD-L1 accumulation on the surface of TAMS in a mouse model of TNBC, consistent with in vitro results. Combinatorial treatment with paclitaxel and an anti-mouse PD-L1 blocking antibody significantly improved the therapeutic efficacy of paclitaxel by reducing tumor burden and increasing the number of tumor-associated cytotoxic T cells. Our results provide a strong rationale for the use of anti–PD-L1 blockade in the treatment of TNBC patients. Furthermore, interrogation of chemotherapy-induced PD-L1 expression in TAMs is warranted to define appropriate patient selection in the use of PD-L1 blockade.-
dc.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America-
dc.subjectReactive oxygen species-
dc.subjectImmune suppression-
dc.subjectProgrammed death ligand-1-
dc.subjectMacrophages-
dc.subjectChemotherapy-
dc.titleReactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.1819473116-
dc.identifier.pmid30770442-
dc.identifier.pmcidPMC6410837-
dc.identifier.scopuseid_2-s2.0-85062645456-
dc.identifier.volume116-
dc.identifier.issue10-
dc.identifier.spage4326-
dc.identifier.epage4335-
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000460242100062-
dc.identifier.issnl0027-8424-

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