서울의대 / 한민국, 장원익, 김인아*
Abstract
Purpose: The poor response of breast cancer to immune checkpoint blockade might result from low immunogenicity and the immune-suppressive tumor microenvironment. We hypothesized that in situ tumor vaccination via radiation therapy (RT) and suppression of immune tolerance via phosphoinositide 3-kinase δ (PI3Kδ) inhibition would enhance the efficacy of immune checkpoint blockade.
Methods and materials: 4T1 murine breast cancer cells were grown in both immune-competent and -deficient BALB/c mice, and tumors were irradiated with 24 Gy in 3 fractions. A PD-1 blockade and a PI3Kαδ inhibitor were then administered every other day for 2 weeks. Fluorescence-activated cell sorting and immunohistochemistry served to monitor subsequent changes in immune cell repertoire.
Results: The triple combination of RT, PD-1 blockade, and PI3Kαδ inhibitor significantly delayed tumor growth. The immune-deficient syngeneic 4T1 murine tumor model failed to show this tumor growth delay. Use of RT and PI3Kαδ inhibitor increased the proportions of CD8+ T cells; PI3Kαδ inhibitor led to a decrease in regulatory T cells and polymorphonuclear myeloid-derived suppressor cells. The triple combination resulted in a remarkable increase in cytotoxic CD8+ T cells, suggesting a prominent immune-modulatory effect. The abscopal effect was most prominent in the triple-combination therapy group, and it correlated with splenic CD8+ T cell accumulation.
Conclusions: These findings collectively indicate that combining RT, PI3Kαδ inhibitor, and PD-1 blockade could be a viable approach, helping to overcome the therapeutic resistance of immunologically cold tumors, such as breast cancer, with an immunosuppressive tumor microenvironment.
방사선치료와 PD-1 억제제, PI3Kαδ 억제제의 삼중병용요법이 단독 혹은 이중병용요법보다 종양의 성장을 억제하는 데에 효과적임을 확인할 수 있었다 방사선치료 범위에 포함되지 않은 부위의 종양의 성장억제 효과인 abscopal effect도 확인할 수 있으며 삼중병용요법에서 그 효과가 가장 뚜렷하였다
Affiliations
Won Ick Chang 1 , Min Guk Han 2 , Mi Hyun Kang 3 , Ji Min Park 2 , Eric Eunshik Kim 3 , Junhyung Bae 3 , Soyeon Ahn 4 , In Ah Kim 5
1 Department of Radiation Oncology, Seoul National University, School of Medicine, Seoul, Republic of Korea; Medical Science Research Institute, Seoul National University Bundang Hospital, Seoul, Republic of Korea.
2 Medical Science Research Institute, Seoul National University Bundang Hospital, Seoul, Republic of Korea; Cancer Research Institute and Department of Tumor Biology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.
3 Medical Science Research Institute, Seoul National University Bundang Hospital, Seoul, Republic of Korea.
4 Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seoul, Republic of Korea.
5 Department of Radiation Oncology, Seoul National University, School of Medicine, Seoul, Republic of Korea; Medical Science Research Institute, Seoul National University Bundang Hospital, Seoul, Republic of Korea; Cancer Research Institute and Department of Tumor Biology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea. Electronic address: inah228@snu.ac.kr.
편집위원
유방암의 면역치료가 효과적이지 못한 이유는 낮은 immunogenicity와 immune-suppressive tumor microenvironment 때문으로 알려져 있다. 본 연구에서는 RT, PI3Kαδ inhibitor, PD-1 blockade를 활용한 삼중병용처리가 cytotoxic CD8+ T cells의 증가와 abscopal effect를 통해 기존의 유방암 치료처항성을 극복하는 효과적인 치료 프로토콜이 될 수 있음을 증명하였다.
2021-09-02 13:22:54
편집위원2
최신 항암면역 치료제와 방사선치료의 병용효과를 연구하기 위해 동물모델을 활용하여 의미 있는 전임상 연구 결과를 발표하였음.
2021-09-02 13:24:09