Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.
Hubei Key Laboratory of Tumour Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.
Clin Transl Oncol. 2021 Sep;23(9):1827-1837. doi: 10.1007/s12094-021-02591-z. Epub 2021 Mar 28.
Poly-(ADP-Ribose)-Polymerase inhibitors (PARPi) were reported as radiosensitizers in non-small cell lung cancer (NSCLC) with wide-type epidermal growth factor receptor (EGFR), but the effects of radiation combined with PARPi were not investigated in EGFR-mutated NSCLC. Moreover, the underlying mechanisms were not well examined. This study aimed to study the efficacy of radiation combined with niraparib in EGFR-mutated NSCLC and explore their influence on the immune system.
Clone formation and apoptosis assay were conducted to explore the effects of niraparib and radiation. Immunofluorescence was conducted to detect the double-strand DNA breaks. Real-time PCR and immunoblotting were employed to evaluate the activation of STING/TBK1/TRF3 pathway and the expression levels of interferon β, CCL5 and CXCL10. Immunocompetent mice model bearing with subcutaneous Lewis lung cancer was established to confirm the results in vivo.
Niraparib and radiation were synergistic to inhibit tumor both in vitro and in vivo. Radiation plus niraparib could activate anti-tumor immunity, which appeared as increased CD8 T lymphocytes and activated STING/TBK1/IRF3 pathway.
PARPi not only as a radiosensitizer inhibited EGFR-mutated NSCLC tumor growth, but also cooperated with radiation to promote anti-tumor immune responses.
多聚（ADP-核糖）聚合酶抑制剂（PARPi）在表皮生长因子受体（EGFR）野生型非小细胞肺癌（NSCLC）中被报道为放射增敏剂，但在 EGFR 突变型 NSCLC 中尚未研究放射与 PARPi 联合使用的效果。此外，其潜在机制也未得到充分研究。本研究旨在研究放射与尼拉帕利联合用于 EGFR 突变型 NSCLC 的疗效，并探讨其对免疫系统的影响。
通过集落形成和细胞凋亡实验来探索尼拉帕利和放射的作用。通过免疫荧光检测双链 DNA 断裂。采用实时 PCR 和免疫印迹来评估 STING/TBK1/TRF3 通路的激活以及干扰素 β、CCL5 和 CXCL10 的表达水平。通过建立携带皮下 Lewis 肺癌的免疫活性小鼠模型来在体内验证结果。
尼拉帕利和放射在体外和体内均协同抑制肿瘤。放射加尼拉帕利可激活抗肿瘤免疫，表现为 CD8 T 淋巴细胞增加和 STING/TBK1/IRF3 通路的激活。
PARPi 不仅作为放射增敏剂抑制 EGFR 突变型 NSCLC 肿瘤生长，还与放射协同促进抗肿瘤免疫反应。
