PI3Kδ/γ inhibitor BR101801 extrinsically potentiates effector CD8+ T cell-dependent antitumor immunity and abscopal effect after local irradiation
Background Radiotherapy enhances antitumor immunity. However, it also induces immunosuppressive responses, which are major hurdles for an effective treatment. Thus, targeting the immunosuppressive tumor microenvironment is essential for enhancing the antitumor immunity after radiotherapy. Retrospect...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e003762.full |
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| author | Tae-Jin Kim Yi Na Yoon Jae-Sung Kim Eunju Lee Young-Ju Kwon Jeong-An Gim |
| author_facet | Tae-Jin Kim Yi Na Yoon Jae-Sung Kim Eunju Lee Young-Ju Kwon Jeong-An Gim |
| author_sort | Tae-Jin Kim |
| collection | DOAJ |
| description | Background Radiotherapy enhances antitumor immunity. However, it also induces immunosuppressive responses, which are major hurdles for an effective treatment. Thus, targeting the immunosuppressive tumor microenvironment is essential for enhancing the antitumor immunity after radiotherapy. Retrospective studies show that a blockade of PI3Kδ and/or γ, which are abundant in leukocytes, exhibits antitumor immune response by attenuating activity of immune suppressive cells, however, the single blockade of PI3Kδ or γ is not sufficient to completely eliminate solid tumor.Methods We used BR101801, PI3Kδ/γ inhibitor in the CT-26 syngeneic mouse model with a subcutaneously implanted tumor. BR101801 was administered daily, and the target tumor site was locally irradiated. We monitored the tumor growth regularly and evaluated the immunological changes using flow cytometry, ELISpot, and transcriptional analysis.Results This study showed that BR101801 combined with irradiation promotes systemic antitumor immunity and abscopal response by attenuating the activity of immune suppressive cells in the CT-26 tumor model. BR101801 combined with irradiation systemically reduced the proliferation of regulatory T cells (Tregs) and enhanced the number of tumor-specific CD8α+ T cells in the tumor microenvironment, thereby leading to tumor regression. Furthermore, the high ratio of CD8α+ T cells to Tregs was maintained for 14 days after irradiation, resulting in remote tumor regression in metastatic lesions, the so-called abscopal effect. Moreover, our transcriptomic analysis showed that BR101801 combined with irradiation promoted the immune-stimulatory tumor microenvironment, suggesting that the combined therapy converts immunologically cold tumors into hot one.Conclusions Our data suggest the first evidence that PI3Kδ/γ inhibition combined with irradiation promotes systemic antitumor immunity against solid tumors, providing the preclinical result of the potential use of PI3Kδ/γ inhibitor as an immune-regulatory radiosensitizer. |
| first_indexed | 2024-03-12T21:41:53Z |
| format | Article |
| id | doaj.art-e7565b1be622423099e5a77c5124d6e7 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T21:41:53Z |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-e7565b1be622423099e5a77c5124d6e72023-07-26T22:30:06ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-003762PI3Kδ/γ inhibitor BR101801 extrinsically potentiates effector CD8+ T cell-dependent antitumor immunity and abscopal effect after local irradiationTae-Jin Kim0Yi Na Yoon1Jae-Sung Kim2Eunju Lee3Young-Ju Kwon4Jeong-An Gim5Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Nowon-gu, Seoul, The Republic of KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Nowon-gu, Seoul, The Republic of KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Nowon-gu, Seoul, The Republic of KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Nowon-gu, Seoul, The Republic of KoreaDivision of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Nowon-gu, Seoul, The Republic of KoreaMedical Science Research Center, College of Medicine, Korea University, Seoul, The Republic of KoreaBackground Radiotherapy enhances antitumor immunity. However, it also induces immunosuppressive responses, which are major hurdles for an effective treatment. Thus, targeting the immunosuppressive tumor microenvironment is essential for enhancing the antitumor immunity after radiotherapy. Retrospective studies show that a blockade of PI3Kδ and/or γ, which are abundant in leukocytes, exhibits antitumor immune response by attenuating activity of immune suppressive cells, however, the single blockade of PI3Kδ or γ is not sufficient to completely eliminate solid tumor.Methods We used BR101801, PI3Kδ/γ inhibitor in the CT-26 syngeneic mouse model with a subcutaneously implanted tumor. BR101801 was administered daily, and the target tumor site was locally irradiated. We monitored the tumor growth regularly and evaluated the immunological changes using flow cytometry, ELISpot, and transcriptional analysis.Results This study showed that BR101801 combined with irradiation promotes systemic antitumor immunity and abscopal response by attenuating the activity of immune suppressive cells in the CT-26 tumor model. BR101801 combined with irradiation systemically reduced the proliferation of regulatory T cells (Tregs) and enhanced the number of tumor-specific CD8α+ T cells in the tumor microenvironment, thereby leading to tumor regression. Furthermore, the high ratio of CD8α+ T cells to Tregs was maintained for 14 days after irradiation, resulting in remote tumor regression in metastatic lesions, the so-called abscopal effect. Moreover, our transcriptomic analysis showed that BR101801 combined with irradiation promoted the immune-stimulatory tumor microenvironment, suggesting that the combined therapy converts immunologically cold tumors into hot one.Conclusions Our data suggest the first evidence that PI3Kδ/γ inhibition combined with irradiation promotes systemic antitumor immunity against solid tumors, providing the preclinical result of the potential use of PI3Kδ/γ inhibitor as an immune-regulatory radiosensitizer.https://jitc.bmj.com/content/10/3/e003762.full |
| spellingShingle | Tae-Jin Kim Yi Na Yoon Jae-Sung Kim Eunju Lee Young-Ju Kwon Jeong-An Gim PI3Kδ/γ inhibitor BR101801 extrinsically potentiates effector CD8+ T cell-dependent antitumor immunity and abscopal effect after local irradiation Journal for ImmunoTherapy of Cancer |
| title | PI3Kδ/γ inhibitor BR101801 extrinsically potentiates effector CD8+ T cell-dependent antitumor immunity and abscopal effect after local irradiation |
| title_full | PI3Kδ/γ inhibitor BR101801 extrinsically potentiates effector CD8+ T cell-dependent antitumor immunity and abscopal effect after local irradiation |
| title_fullStr | PI3Kδ/γ inhibitor BR101801 extrinsically potentiates effector CD8+ T cell-dependent antitumor immunity and abscopal effect after local irradiation |
| title_full_unstemmed | PI3Kδ/γ inhibitor BR101801 extrinsically potentiates effector CD8+ T cell-dependent antitumor immunity and abscopal effect after local irradiation |
| title_short | PI3Kδ/γ inhibitor BR101801 extrinsically potentiates effector CD8+ T cell-dependent antitumor immunity and abscopal effect after local irradiation |
| title_sort | pi3kδ γ inhibitor br101801 extrinsically potentiates effector cd8 t cell dependent antitumor immunity and abscopal effect after local irradiation |
| url | https://jitc.bmj.com/content/10/3/e003762.full |
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