{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:58:12Z","timestamp":1791374292594,"version":"4.3.1"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2020,11,1]],"date-time":"2020-11-01T00:00:00Z","timestamp":1604188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100001755","name":"Mesothelioma Applied Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001755","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009812","name":"Princess Margaret Cancer Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009812","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008732","name":"Uehara Memorial Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008732","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Increasing evidence indicates that local hypofractionated radiotherapy (LRT) can elicit both immunogenic and immunosuppressive local and systemic immune responses. We thus hypothesized that blockade of LRT-induced immunosuppressive responses could augment the antitumor effects and induce an abscopal response. In this study, we found that the upregulation of Foxp3+ regulatory T cells (Tregs) in the mesothelioma tumor microenvironment after nonablative oligofractionated irradiation significantly limited the success of irradiation. Using DEREG mice, which allow conditional and efficient depletion of Foxp3+ Tregs by diphtheria toxin injection, we observed that transient Foxp3+ Treg depletion immediately after nonablative oligofractionated irradiation provided synergistic local control and biased the T cell repertoire toward central and effector memory T cells, resulting in long-term cure. Furthermore, this combination therapy showed significant abscopal effect on the nonirradiated tumors in a concomitant model of mesothelioma through systemic activation of cytotoxic T cells and enhanced production of IFN-\u03b3 and granzyme B. Although local control was preserved with one fraction of nonablative irradiation, three fractions were required to generate the abscopal effect. PD-1 and CTLA-4 were upregulated on tumor-infiltrating CD4+ and CD8+ T cells in irradiated and nonirradiated tumors, suggesting that immune checkpoint inhibitors could be beneficial after LRT and Foxp3+ Treg depletion. Our findings are applicable to the strategy of immuno-radiotherapy for generating optimal antitumor immune responses in the clinical setting. Targeting Tregs immediately after a short course of irradiation could have a major impact on the local response to irradiation and its abscopal effect.<\/jats:p>","DOI":"10.4049\/jimmunol.2000487","type":"journal-article","created":{"date-parts":[[2020,9,18]],"date-time":"2020-09-18T20:20:55Z","timestamp":1600460455000},"page":"2519-2531","source":"Crossref","is-referenced-by-count":25,"title":["Foxp3+ Regulatory T Cell Depletion after Nonablative Oligofractionated Irradiation Boosts the Abscopal Effects in Murine Malignant Mesothelioma"],"prefix":"10.1093","volume":"205","author":[{"given":"Mikihiro","family":"Kohno","sequence":"first","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University of Toronto , Toronto, Ontario M5G 2C4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Murakami","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University of Toronto , Toronto, Ontario M5G 2C4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4803-9361","authenticated-orcid":false,"given":"Licun","family":"Wu","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University of Toronto , Toronto, Ontario M5G 2C4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Lin","family":"Chan","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University of Toronto , Toronto, Ontario M5G 2C4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2915-6802","authenticated-orcid":false,"given":"Zhihong","family":"Yun","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University of Toronto , Toronto, Ontario M5G 2C4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4531-3396","authenticated-orcid":false,"given":"B C John","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto , Toronto, Ontario M5G 2C1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"de Perrot","sequence":"additional","affiliation":[{"name":"Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University of Toronto , Toronto, Ontario M5G 2C4 ,","place":["Canada"]},{"name":"Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto , Toronto, Ontario M5G 2C4 ,","place":["Canada"]},{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5G 2C4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,11,1]]},"reference":[{"key":"2025030417505605300_r1","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.athoracsur.2017.09.036","article-title":"National trends in the epidemiology of malignant pleural mesothelioma: a national cancer data base study","volume":"105","author":"Saddoughi","year":"2018","journal-title":"Ann. 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