N Zhang1, Y Gao1, Z Zeng1, Y Luo1, X Jiang1, J Zhang1,2,3, J Li1, J Zhang1,2,3, Y Gong4,5, C Xie6,7,8. 1. Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China. 2. Hubei Key Laboratory of Tumour Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China. 3. Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China. 4. Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China. yan.gong@whu.edu.cn. 5. Human Genetics Resource Preservation Center of Hubei Province, Human Genetics Resource Preservation Center of Wuhan University, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China. yan.gong@whu.edu.cn. 6. Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China. chxie_65@whu.edu.cn. 7. Hubei Key Laboratory of Tumour Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China. chxie_65@whu.edu.cn. 8. Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China. chxie_65@whu.edu.cn.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: PARPi not only as a radiosensitizer inhibited EGFR-mutated NSCLC tumor growth, but also cooperated with radiation to promote anti-tumor immune responses.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: PARPi not only as a radiosensitizer inhibited EGFR-mutated NSCLC tumor growth, but also cooperated with radiation to promote anti-tumor immune responses.
Authors: Amit A Lugade; Elizabeth W Sorensen; Scott A Gerber; James P Moran; John G Frelinger; Edith M Lord Journal: J Immunol Date: 2008-03-01 Impact factor: 5.422
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