CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages
Tumor-associated macrophages can account for up to 50% of the tumor mass in breast cancer patients and high TAM density is associated with poor clinical prognosis. Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic...
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| description | Tumor-associated macrophages can account for up to 50% of the tumor mass in breast cancer patients and high TAM density is associated with poor clinical prognosis. Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic benefit. Our studies in primary human macrophages and murine breast TAMs suggest that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) reprograms the activation profile of TAMs from tumor-promoting to tumor-inhibiting. We show that CDDO-Me treatment inhibits expression of IL-10 and VEGF in stimulated human M2 macrophages and TAMs but increases expression of TNF-α and IL-6. Surface expression of CD206 and CD163, which are characteristic of M2 activation, is significantly attenuated by CDDO-Me. In contrast, CDDO-Me up-regulates surface expression of HLA-DR and CD80, which are markers of M1 activation, and importantly potentiates macrophage activation of autologous T cells but inhibits endothelial cell vascularization. These results show for the first time that CDDO-Me redirects activation of M2 macrophages and TAMs from immune-suppressive to immune-stimulatory, and implicate a role for CDDO-Me as an immunotherapeutic in the treatment of breast and potentially other types of cancer. |
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Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic benefit. Our studies in primary human macrophages and murine breast TAMs suggest that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) reprograms the activation profile of TAMs from tumor-promoting to tumor-inhibiting. We show that CDDO-Me treatment inhibits expression of IL-10 and VEGF in stimulated human M2 macrophages and TAMs but increases expression of TNF-α and IL-6. Surface expression of CD206 and CD163, which are characteristic of M2 activation, is significantly attenuated by CDDO-Me. In contrast, CDDO-Me up-regulates surface expression of HLA-DR and CD80, which are markers of M1 activation, and importantly potentiates macrophage activation of autologous T cells but inhibits endothelial cell vascularization. These results show for the first time that CDDO-Me redirects activation of M2 macrophages and TAMs from immune-suppressive to immune-stimulatory, and implicate a role for CDDO-Me as an immunotherapeutic in the treatment of breast and potentially other types of cancer.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0149600</identifier><identifier>PMID: 26918785</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Angiogenesis ; Animals ; Antigens ; Biology and Life Sciences ; Biomarkers, Tumor - genetics ; Breast cancer ; Breast Neoplasms - genetics ; Breast Neoplasms - immunology ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cancer ; Cancer therapies ; CD163 antigen ; CD80 antigen ; Cell activation ; Cell Proliferation - drug effects ; Cytokines ; Cytokines - genetics ; Cytokines - metabolism ; Development and progression ; Endothelial cells ; Female ; Flow cytometry ; Gene Expression Regulation, Neoplastic - drug effects ; Genetic aspects ; Gynecology ; Health aspects ; Histocompatibility antigen HLA ; Humans ; Interleukin 10 ; Interleukin 6 ; Lymphocytes ; Lymphocytes T ; Macrophage Activation - drug effects ; Macrophages ; Macrophages - cytology ; Macrophages - drug effects ; Macrophages - immunology ; Macrophages - metabolism ; Medical research ; Medicine ; Medicine and Health Sciences ; Metastases ; Metastasis ; Mice ; Obstetrics ; Oleanolic Acid - analogs & derivatives ; Oleanolic Acid - pharmacology ; Physiological aspects ; Prognosis ; Research and Analysis Methods ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Rodents ; Studies ; T-Lymphocytes - cytology ; Tumor necrosis factor ; Tumor necrosis factor-α ; Tumors ; Vascular endothelial growth factor ; Vascularization</subject><ispartof>PloS one, 2016-02, Vol.11 (2), p.e0149600</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Ball 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>2016 Ball et al 2016 Ball et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-bea46218267c66c2086c03223edf9142fbb15792a69b3de9101405c63ff292bb3</citedby><cites>FETCH-LOGICAL-c692t-bea46218267c66c2086c03223edf9142fbb15792a69b3de9101405c63ff292bb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769014/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769014/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26918785$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Mattei, Fabrizio</contributor><creatorcontrib>Ball, Michael S</creatorcontrib><creatorcontrib>Shipman, Emilie P</creatorcontrib><creatorcontrib>Kim, Hyunjung</creatorcontrib><creatorcontrib>Liby, Karen T</creatorcontrib><creatorcontrib>Pioli, Patricia A</creatorcontrib><title>CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Tumor-associated macrophages can account for up to 50% of the tumor mass in breast cancer patients and high TAM density is associated with poor clinical prognosis. Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic benefit. Our studies in primary human macrophages and murine breast TAMs suggest that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) reprograms the activation profile of TAMs from tumor-promoting to tumor-inhibiting. We show that CDDO-Me treatment inhibits expression of IL-10 and VEGF in stimulated human M2 macrophages and TAMs but increases expression of TNF-α and IL-6. Surface expression of CD206 and CD163, which are characteristic of M2 activation, is significantly attenuated by CDDO-Me. In contrast, CDDO-Me up-regulates surface expression of HLA-DR and CD80, which are markers of M1 activation, and importantly potentiates macrophage activation of autologous T cells but inhibits endothelial cell vascularization. These results show for the first time that CDDO-Me redirects activation of M2 macrophages and TAMs from immune-suppressive to immune-stimulatory, and implicate a role for CDDO-Me as an immunotherapeutic in the treatment of breast and potentially other types of cancer.</description><subject>Angiogenesis</subject><subject>Animals</subject><subject>Antigens</subject><subject>Biology and Life Sciences</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - immunology</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>CD163 antigen</subject><subject>CD80 antigen</subject><subject>Cell activation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cytokines</subject><subject>Cytokines - genetics</subject><subject>Cytokines - metabolism</subject><subject>Development and progression</subject><subject>Endothelial cells</subject><subject>Female</subject><subject>Flow cytometry</subject><subject>Gene Expression Regulation, Neoplastic - 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genetics</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - immunology</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>CD163 antigen</topic><topic>CD80 antigen</topic><topic>Cell activation</topic><topic>Cell Proliferation - drug effects</topic><topic>Cytokines</topic><topic>Cytokines - genetics</topic><topic>Cytokines - metabolism</topic><topic>Development and progression</topic><topic>Endothelial cells</topic><topic>Female</topic><topic>Flow cytometry</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Genetic aspects</topic><topic>Gynecology</topic><topic>Health aspects</topic><topic>Histocompatibility antigen HLA</topic><topic>Humans</topic><topic>Interleukin 10</topic><topic>Interleukin 6</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Macrophage Activation - drug effects</topic><topic>Macrophages</topic><topic>Macrophages - 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Because TAMs enhance tumor growth, development, and metastatic potential, redirection of TAM activation may have significant therapeutic benefit. Our studies in primary human macrophages and murine breast TAMs suggest that the synthetic oleanane triterpenoid CDDO-methyl ester (CDDO-Me) reprograms the activation profile of TAMs from tumor-promoting to tumor-inhibiting. We show that CDDO-Me treatment inhibits expression of IL-10 and VEGF in stimulated human M2 macrophages and TAMs but increases expression of TNF-α and IL-6. Surface expression of CD206 and CD163, which are characteristic of M2 activation, is significantly attenuated by CDDO-Me. In contrast, CDDO-Me up-regulates surface expression of HLA-DR and CD80, which are markers of M1 activation, and importantly potentiates macrophage activation of autologous T cells but inhibits endothelial cell vascularization. These results show for the first time that CDDO-Me redirects activation of M2 macrophages and TAMs from immune-suppressive to immune-stimulatory, and implicate a role for CDDO-Me as an immunotherapeutic in the treatment of breast and potentially other types of cancer.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26918785</pmid><doi>10.1371/journal.pone.0149600</doi><oa>free_for_read</oa></addata></record> |
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| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Angiogenesis Animals Antigens Biology and Life Sciences Biomarkers, Tumor - genetics Breast cancer Breast Neoplasms - genetics Breast Neoplasms - immunology Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer Cancer therapies CD163 antigen CD80 antigen Cell activation Cell Proliferation - drug effects Cytokines Cytokines - genetics Cytokines - metabolism Development and progression Endothelial cells Female Flow cytometry Gene Expression Regulation, Neoplastic - drug effects Genetic aspects Gynecology Health aspects Histocompatibility antigen HLA Humans Interleukin 10 Interleukin 6 Lymphocytes Lymphocytes T Macrophage Activation - drug effects Macrophages Macrophages - cytology Macrophages - drug effects Macrophages - immunology Macrophages - metabolism Medical research Medicine Medicine and Health Sciences Metastases Metastasis Mice Obstetrics Oleanolic Acid - analogs & derivatives Oleanolic Acid - pharmacology Physiological aspects Prognosis Research and Analysis Methods RNA, Messenger - genetics RNA, Messenger - metabolism Rodents Studies T-Lymphocytes - cytology Tumor necrosis factor Tumor necrosis factor-α Tumors Vascular endothelial growth factor Vascularization |
| title | CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T18%3A23%3A44IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=CDDO-Me%20Redirects%20Activation%20of%20Breast%20Tumor%20Associated%20Macrophages&rft.jtitle=PloS%20one&rft.au=Ball,%20Michael%20S&rft.date=2016-02-26&rft.volume=11&rft.issue=2&rft.spage=e0149600&rft.pages=e0149600-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0149600&rft_dat=%3Cgale_plos_%3EA444363814%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1771271649&rft_id=info:pmid/26918785&rft_galeid=A444363814&rft_doaj_id=oai_doaj_org_article_6ec57f19370c49e5962994da733bd5eb&rfr_iscdi=true |