PARP inhibitor plus radiotherapy reshapes an inflamed tumor microenvironment that sensitizes small cell lung cancer to the anti-PD-1 immunotherapy. (1st October 2022)

• Record Type: Journal Article
• Authors: Zhang, Nannan; Gao, Yanping; Huang, Zhengrong; Dai, Panpan; Luo, Yuan; Wu, Qiuji; Jiang, Xueping; Sun, Wenjie; Zhang, Jianguo; Han, Linzhi; Zhang, Jinfang; Gong, Yan; Xie, Conghua
• Is Part Of: Cancer letters. Volume 545(2022)
• Publication Date: 2022-10-01
• Subjects: Niraparib -- cGAS/STING -- CD8+ T cell -- Immunogenic cell death -- Combined therapy; SCLC Small cell lung cancer -- ICIs immune checkpoint inhibitors -- TME Tumor microenvironment -- RT Radiotherapy -- ds-DNA double-strand DNA -- PARP Poly (ADP-ribose) polymerase -- ICD immunogenic cell death -- HMGB high mobility group box protein -- ATP adenosine triphosphate -- AST aspartate amino transferase -- ALT alanine amino transferase -- CRT calreticulin; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.215852
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Small cell lung cancer (SCLC) is a highly malignant tumor with extremely poor prognosis. The treatment strategy is very limited, and patient outcomes remain dismal with the 5-year survival rate being mere 3–6%. Thus, novel therapeutic strategies for SCLC patients are urgently needed. In this study, we found that the triple-therapy of poly (ADP-ribose) polymerase (PARP) inhibitor, radiotherapy (RT) and anti -PD-1 treatment significantly inhibited tumor growth and prolonged survival in the syngeneic SCLC models in immunocompetent C57BL/6 mice. Mechanistically, we demonstrated that the combination of PARP inhibitor niraparib and RT reshaped an inflamed tumor microenvironment, including activation of the cGAS/STING immune response pathway, induction of immunogenic cell death, and upregulation of PD-L1 on tumor cells. Furthermore, this triple-therapy substantially augmented CD8 + T cell infiltration and activation, and enhanced anti-tumor effects as revealed by increased median survival time and reduced tumor volume without additional myelosuppression or hepatic injury. Together, our studies demonstrated that PARP inhibitor combined with RT potentiated anti-tumor immunity and enhanced the efficacy of anti -PD-1 immunotherapy in preclinical study, which provided a promising therapeutic strategy for SCLC patients in clinic. Highlights: PARPI plus radiation further activated cGAS/STING pathway than single treatment. PARPI plus radiation upregulated the expression of PD-L1. PARPI plus radiation sensitizes small cell lung cancer to anti -PD-1 immunotherapy.