Entinostat decreases immune suppression to promote antitumor responses in a HER2+ breast tumor microenvironment

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dc.contributor.authorSidiropoulos, Dimitrios N.
dc.contributor.authorRafie, Christine I.
dc.contributor.authorJang, Julie K.
dc.contributor.authorCastanon, Sofi
dc.contributor.authorBaugh, Aaron G.
dc.contributor.authorGonzalez, Edgar
dc.contributor.authorChristmas, Brian J.
dc.contributor.authorNarumi, Valerie H.
dc.contributor.authorDavis-Marcisak, Emily F.
dc.contributor.authorSharma, Gaurav
dc.contributor.authorBigelow, Emma
dc.contributor.authorVaghasia, Ajay
dc.contributor.authorGupta, Anuj
dc.contributor.authorSkaist, Alyza
dc.contributor.authorConsidine, Michael
dc.contributor.authorWheelan, Sarah J.
dc.contributor.authorKumar Ganesan, Sathish
dc.contributor.authorYu, Min
dc.contributor.authorYegnasubramanian, Srinivasan
dc.contributor.authorStearns, Vered
dc.contributor.authorConnolly, Roisin M.
dc.contributor.authorGaykalova, Daria A.
dc.contributor.authorKagohara, Luciane T.
dc.contributor.authorJaffee, Elizabeth M.
dc.contributor.authorFertig, Elana J.
dc.contributor.authorRoussos Torres, Evanthia T.
dc.contributor.funderNational Institutes of Healthen
dc.contributor.funderNational Cancer Instituteen
dc.contributor.funderLustgarten Foundationen
dc.contributor.funderStand Up To Canceren
dc.contributor.funderAmerican Association for Cancer Researchen
dc.contributor.funderAmerican Cancer Societyen
dc.contributor.funderBloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Universityen
dc.contributor.funderSkip Viragh Foundationen
dc.contributor.funderCommonwealth Foundation for Cancer Research Foundationen
dc.contributor.funderAlleghany Foundationen
dc.contributor.funderTower Cancer Research Foundationen
dc.contributor.funderFred L. Emerson Foundationen
dc.contributor.funderSidney Kimmel Comprehensive Cancer Centeren
dc.contributor.funderMaryland General Assembly, United Statesen
dc.date.accessioned2022-06-30T08:31:09Z
dc.date.available2022-06-30T08:31:09Z
dc.date.issued2022-05-03
dc.date.updated2022-06-29T15:33:53Z
dc.description.abstractTherapeutic combinations to alter immunosuppressive, solid tumor microenvironments (TME), such as in breast cancer, are essential to improve responses to immune checkpoint inhibitors (ICI). Entinostat, an oral histone deacetylase inhibitor, has been shown to improve responses to ICIs in various tumor models with immunosuppressive TMEs. The precise and comprehensive alterations to the TME induced by entinostat remain unknown. Here, we employed single-cell RNA sequencing on HER2-overexpressing breast tumors from mice treated with entinostat and ICIs to fully characterize changes across multiple cell types within the TME. This analysis demonstrates that treatment with entinostat induced a shift from a protumor to an antitumor TME signature, characterized predominantly by changes in myeloid cells. We confirmed myeloid-derived suppressor cells (MDSC) within entinostat-treated tumors associated with a less suppressive granulocytic (G)-MDSC phenotype and exhibited altered suppressive signaling that involved the NFκB and STAT3 pathways. In addition to MDSCs, tumor-associated macrophages were epigenetically reprogrammed from a protumor M2-like phenotype toward an antitumor M1-like phenotype, which may be contributing to a more sensitized TME. Overall, our in-depth analysis suggests that entinostat-induced changes on multiple myeloid cell types reduce immunosuppression and increase antitumor responses, which, in turn, improve sensitivity to ICIs. Sensitization of the TME by entinostat could ultimately broaden the population of patients with breast cancer who could benefit from ICIs.en
dc.description.sponsorshipNIH (NCI R01CA184926; P50CA062924; NCI R01CA177669; NCI U01 CA253403; NCI 5T32 CA009071–34; NCI P30 CA006973; NIDCR R01DE27809; NCI P30 CA014089); American Association for Cancer Research (Stand Up To Cancer - Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant SU2C-AACR-DT14–14); Lustgarten Foundation (Research Investigator's Award Program); American Cancer Society (Broccoli Foundation Research Scholarship Grant, RSG-21-020-01-MPC); Tower Cancer Research Foundation (Career Development Award); Sidney Kimmel Comprehensive Cancer Center (MacMillan Pathway to Independence Fellowship); Maryland General Assembly, United States (Cigarette Restitution Fund)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationSidiropoulos, D. N., Rafie, C. I., Jang, J. K., Castanon, S., Baugh, A. G., Gonzalez, E., Christmas, B. J., Narumi, V. H., Davis-Marcisak, E. F., Sharma, G., Bigelow, E., Vaghasia, A., Gupta, A., Skaist, A., Considine, M., Wheelan, S. J., Kumar Ganesan, S., Yu, M., Yegnasubramanian, S., Stearns, V., Connolly, R. M., Gaykalova, D. A., Kagohara, L. T., Jaffee, E. M., Fertig, E. J. and Roussos Torres, E. T. (2022) 'Entinostat decreases immune suppression to promote antitumor responses in a HER2+ breast tumor microenvironment', Cancer Immunology Research, 10(5), pp. 656-669. doi: 10.1158/2326-6066.CIR-21-0170en
dc.identifier.doi10.1158/2326-6066.CIR-21-0170en
dc.identifier.eissn2326-6074
dc.identifier.endpage669en
dc.identifier.issn2326-6066
dc.identifier.issued5en
dc.identifier.journaltitleCancer Immunology Researchen
dc.identifier.startpage656en
dc.identifier.urihttps://hdl.handle.net/10468/13332
dc.identifier.volume10en
dc.language.isoenen
dc.publisherAmerican Association for Cancer Researchen
dc.rights© 2022, American Association for Cancer Research.en
dc.subjectImmune checkpoint inhibitorsen
dc.subjectEpigeneticsen
dc.subjectEntinostaten
dc.subjectNivolumaben
dc.subjectIpilimumaben
dc.titleEntinostat decreases immune suppression to promote antitumor responses in a HER2+ breast tumor microenvironmenten
dc.typeArticle (peer-reviewed)en
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