Radiation enhanced the local and distant anti-tumor efficacy in dual immune checkpoint blockade therapy in osteosarcoma
Radiation therapy has been long utilized as localized cancer treatment. Recent studies have also demonstrated that it has a distant effect by the enhanced immunity, but it rarely occurs. The purpose of this study was to investigate whether X-ray irradiation combined with anti-PD-L1 and anti-CTLA-4 a...
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| creator | Takahashi, Yutaka Yasui, Tomohiro Tamari, Keisuke Minami, Kazumasa Otani, Keisuke Isohashi, Fumiaki Seo, Yuji Kambe, Ryosuke Koizumi, Masahiko Ogawa, Kazuhiko |
| description | Radiation therapy has been long utilized as localized cancer treatment. Recent studies have also demonstrated that it has a distant effect by the enhanced immunity, but it rarely occurs. The purpose of this study was to investigate whether X-ray irradiation combined with anti-PD-L1 and anti-CTLA-4 antibodies (P1C4) provides a higher probability of this distant effect as well as enhanced local antitumor efficacy for osteosarcoma. LM8 mouse osteosarcoma cells were inoculated into both legs of C3H mice assigned to one of four groups, namely no treatment (No Tx), P1C4, X-ray irradiation (RAD) to the leg of one side, and combination (COMB) groups. Survival and treatment-related immune molecular changes were analyzed. Administration of P1C4 produced a tumor growth delay on day 30 in 18% of the mice. In contrast, combination therapy produced the strongest tumor growth inhibition not only at the irradiated tumor but also at unirradiated tumor in 67% of the mice. Accordingly, lung metastasis in the COMB group was strongly reduced by 98%, with a significant survival benefit. Unirradiated tumor in mice in the COMB group significantly recruited CD8 + tumor-infiltrating lymphocytes with a moderate reduction of Treg, producing a significant increase in the CD8/Treg ratio. These results suggest that radiation enhances the efficacy of P1C4 treatment against distant metastasis as well as local control in osteosarcoma. Our data suggest that radiation therapy combined with dual checkpoint blockade may be a promising therapeutic option for osteosarcoma. |
| doi_str_mv | 10.1371/journal.pone.0189697 |
| format | Article |
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Recent studies have also demonstrated that it has a distant effect by the enhanced immunity, but it rarely occurs. The purpose of this study was to investigate whether X-ray irradiation combined with anti-PD-L1 and anti-CTLA-4 antibodies (P1C4) provides a higher probability of this distant effect as well as enhanced local antitumor efficacy for osteosarcoma. LM8 mouse osteosarcoma cells were inoculated into both legs of C3H mice assigned to one of four groups, namely no treatment (No Tx), P1C4, X-ray irradiation (RAD) to the leg of one side, and combination (COMB) groups. Survival and treatment-related immune molecular changes were analyzed. Administration of P1C4 produced a tumor growth delay on day 30 in 18% of the mice. In contrast, combination therapy produced the strongest tumor growth inhibition not only at the irradiated tumor but also at unirradiated tumor in 67% of the mice. Accordingly, lung metastasis in the COMB group was strongly reduced by 98%, with a significant survival benefit. Unirradiated tumor in mice in the COMB group significantly recruited CD8 + tumor-infiltrating lymphocytes with a moderate reduction of Treg, producing a significant increase in the CD8/Treg ratio. These results suggest that radiation enhances the efficacy of P1C4 treatment against distant metastasis as well as local control in osteosarcoma. Our data suggest that radiation therapy combined with dual checkpoint blockade may be a promising therapeutic option for osteosarcoma.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0189697</identifier><identifier>PMID: 29253865</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Antibodies ; Anticancer properties ; Antitumor activity ; Biocompatibility ; Biology and Life Sciences ; Bone cancer ; Breast cancer ; Cancer ; Cancer metastasis ; Cancer therapies ; CD8 antigen ; CTLA-4 protein ; Drug dosages ; Drug therapy ; Effectiveness ; Engineering ; Growth inhibition ; Health aspects ; Health physics ; Immune checkpoint ; Immunity ; Immunoglobulins ; Immunology ; Immunotherapy ; Irradiation ; Legs ; Lungs ; Lymphocytes ; Lymphocytes T ; Medicine ; Medicine and Health Sciences ; Melanoma ; Metastases ; Metastasis ; Mice ; Oncology ; Osteosarcoma ; Osteosarcoma cells ; Pathogens ; PD-L1 protein ; Physics ; Radiation ; Radiation (Physics) ; Radiation therapy ; Radiotherapy ; Sarcoma ; Survival ; Tumor-infiltrating lymphocytes ; Tumors ; University graduates ; X ray irradiation</subject><ispartof>PloS one, 2017-12, Vol.12 (12), p.e0189697-e0189697</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Takahashi 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>2017 Takahashi et al 2017 Takahashi et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6037-a01aa58d81ae2ba9690ef02381fc7dc8f278dc7b2c4b51dd5884b5c2b30e8c8a3</citedby><cites>FETCH-LOGICAL-c6037-a01aa58d81ae2ba9690ef02381fc7dc8f278dc7b2c4b51dd5884b5c2b30e8c8a3</cites><orcidid>0000-0002-4311-2278</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/PMC5734786/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734786/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23864,27922,27923,53789,53791,79370,79371</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29253865$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Amendola, Roberto</contributor><creatorcontrib>Takahashi, Yutaka</creatorcontrib><creatorcontrib>Yasui, Tomohiro</creatorcontrib><creatorcontrib>Tamari, Keisuke</creatorcontrib><creatorcontrib>Minami, Kazumasa</creatorcontrib><creatorcontrib>Otani, Keisuke</creatorcontrib><creatorcontrib>Isohashi, Fumiaki</creatorcontrib><creatorcontrib>Seo, Yuji</creatorcontrib><creatorcontrib>Kambe, Ryosuke</creatorcontrib><creatorcontrib>Koizumi, Masahiko</creatorcontrib><creatorcontrib>Ogawa, Kazuhiko</creatorcontrib><title>Radiation enhanced the local and distant anti-tumor efficacy in dual immune checkpoint blockade therapy in osteosarcoma</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Radiation therapy has been long utilized as localized cancer treatment. 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Our data suggest that radiation therapy combined with dual checkpoint blockade may be a promising therapeutic option for osteosarcoma.</description><subject>Antibodies</subject><subject>Anticancer properties</subject><subject>Antitumor activity</subject><subject>Biocompatibility</subject><subject>Biology and Life Sciences</subject><subject>Bone cancer</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer metastasis</subject><subject>Cancer therapies</subject><subject>CD8 antigen</subject><subject>CTLA-4 protein</subject><subject>Drug dosages</subject><subject>Drug therapy</subject><subject>Effectiveness</subject><subject>Engineering</subject><subject>Growth inhibition</subject><subject>Health aspects</subject><subject>Health physics</subject><subject>Immune 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enhanced the local and distant anti-tumor efficacy in dual immune checkpoint blockade therapy in osteosarcoma</title><author>Takahashi, Yutaka ; Yasui, Tomohiro ; Tamari, Keisuke ; Minami, Kazumasa ; Otani, Keisuke ; Isohashi, Fumiaki ; Seo, Yuji ; Kambe, Ryosuke ; Koizumi, Masahiko ; Ogawa, Kazuhiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6037-a01aa58d81ae2ba9690ef02381fc7dc8f278dc7b2c4b51dd5884b5c2b30e8c8a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Antibodies</topic><topic>Anticancer properties</topic><topic>Antitumor activity</topic><topic>Biocompatibility</topic><topic>Biology and Life Sciences</topic><topic>Bone cancer</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer metastasis</topic><topic>Cancer therapies</topic><topic>CD8 antigen</topic><topic>CTLA-4 protein</topic><topic>Drug dosages</topic><topic>Drug 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Recent studies have also demonstrated that it has a distant effect by the enhanced immunity, but it rarely occurs. The purpose of this study was to investigate whether X-ray irradiation combined with anti-PD-L1 and anti-CTLA-4 antibodies (P1C4) provides a higher probability of this distant effect as well as enhanced local antitumor efficacy for osteosarcoma. LM8 mouse osteosarcoma cells were inoculated into both legs of C3H mice assigned to one of four groups, namely no treatment (No Tx), P1C4, X-ray irradiation (RAD) to the leg of one side, and combination (COMB) groups. Survival and treatment-related immune molecular changes were analyzed. Administration of P1C4 produced a tumor growth delay on day 30 in 18% of the mice. In contrast, combination therapy produced the strongest tumor growth inhibition not only at the irradiated tumor but also at unirradiated tumor in 67% of the mice. Accordingly, lung metastasis in the COMB group was strongly reduced by 98%, with a significant survival benefit. Unirradiated tumor in mice in the COMB group significantly recruited CD8 + tumor-infiltrating lymphocytes with a moderate reduction of Treg, producing a significant increase in the CD8/Treg ratio. These results suggest that radiation enhances the efficacy of P1C4 treatment against distant metastasis as well as local control in osteosarcoma. Our data suggest that radiation therapy combined with dual checkpoint blockade may be a promising therapeutic option for osteosarcoma.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29253865</pmid><doi>10.1371/journal.pone.0189697</doi><tpages>e0189697</tpages><orcidid>https://orcid.org/0000-0002-4311-2278</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | PloS one, 2017-12, Vol.12 (12), p.e0189697-e0189697 |
| issn | 1932-6203 1932-6203 |
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| source | DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Antibodies Anticancer properties Antitumor activity Biocompatibility Biology and Life Sciences Bone cancer Breast cancer Cancer Cancer metastasis Cancer therapies CD8 antigen CTLA-4 protein Drug dosages Drug therapy Effectiveness Engineering Growth inhibition Health aspects Health physics Immune checkpoint Immunity Immunoglobulins Immunology Immunotherapy Irradiation Legs Lungs Lymphocytes Lymphocytes T Medicine Medicine and Health Sciences Melanoma Metastases Metastasis Mice Oncology Osteosarcoma Osteosarcoma cells Pathogens PD-L1 protein Physics Radiation Radiation (Physics) Radiation therapy Radiotherapy Sarcoma Survival Tumor-infiltrating lymphocytes Tumors University graduates X ray irradiation |
| title | Radiation enhanced the local and distant anti-tumor efficacy in dual immune checkpoint blockade therapy in osteosarcoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-14T00%3A46%3A11IST&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=Radiation%20enhanced%20the%20local%20and%20distant%20anti-tumor%20efficacy%20in%20dual%20immune%20checkpoint%20blockade%20therapy%20in%20osteosarcoma&rft.jtitle=PloS%20one&rft.au=Takahashi,%20Yutaka&rft.date=2017-12-18&rft.volume=12&rft.issue=12&rft.spage=e0189697&rft.epage=e0189697&rft.pages=e0189697-e0189697&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0189697&rft_dat=%3Cgale_plos_%3EA519362663%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=1978297729&rft_id=info:pmid/29253865&rft_galeid=A519362663&rft_doaj_id=oai_doaj_org_article_481dfd72f2354a8e823c81657e99675a&rfr_iscdi=true |