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  • [J Immunother Cancer .] PI3Kδ/γ inhibitor BR101801 extrinsically potentiates effector CD8+ T cell-dependent antitumor immunity and abscopal effect after local irradiationPI3Kδ/γ 저해제를 통한 방사선면역치료효과 연구

    KIRAMS / 윤이나, 김재성*

  • 출처
    J Immunother Cancer .
  • 등재일
    2022 Mar
  • 저널이슈번호
    10(3):e003762. doi: 10.1136/jitc-2021-003762.
  • 내용

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    Abstract
    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.

     

     

    Affiliations

    Yi Na Yoon # 1, Eunju Lee # 1 2, Young-Ju Kwon 1 3, Jeong-An Gim 4, Tae-Jin Kim 5, Jae-Sung Kim 5 3
    1Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Nowon-gu, Seoul, The Republic of Korea.
    2Department of Biochemistry and Molecular Biology, College of Medicine, Korea University, Seongbuk-gu, The Republic of Korea.
    3Radiological and Medico-Oncological Sciences, University of Science and Technology, Yuseong-gu, Daejeon, The Republic of Korea.
    4Medical Science Research Center, College of Medicine, Korea University, Seoul, The Republic of Korea.
    5Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Nowon-gu, Seoul, The Republic of Korea jaesung@kirams.re.kr anaros33@kirams.re.kr.
    #Contributed equally.

     

  • 키워드
    immunotherapy; lymphocytes, tumor-infiltrating; radioimmunotherapy; radiotherapy.
  • 편집위원

    방사선치료 시 발생하는 면역억제반응은 치료효율 저하의 원인으로 작용하며, immunosuppressive tumor microenvironment를 표적하는 것은 방사선치료 후의 antitumor immunity를 증가시키는 효과적인 수단으로 작용한다. 본 연구는 방사선과 PI3Kδ/γ 저해제(BR101801)를 활용한 병용치료가 antitumor immunity를 촉진할 수 있음을 규명하였다.

    2022-11-01 16:00:52

  • 편집위원2

    PI3Kδ/γ 저해제를 통한 방사선면역치료효과 연구에 대한 흥미로운 결과이며, 새로운 PI3Kδ/γ 저해제가 abscopal effect에 영향을 미치는 것에 대한 연구 결과임.

    2022-11-01 16:01:34

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