Xiaomei Gong1, Xuefei Li2, Tao Jiang2, Huikang Xie3, Zhengfei Zhu4, Fei Zhou2, Caicun Zhou5. 1. Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. 2. Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. 3. Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. 4. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China. 5. Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. Electronic address: zhoucc20157@sina.com.
Abstract
INTRODUCTION: Immune escape frequently occurs and restricts the durability of the antitumor immune response to radiotherapy. Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) are important immune checkpoint molecules that could cause tumor cells to escape the host immune response. The aim of the study was to explore the role of PD-L1 in radioresistance and the antitumor effect of combined radiotherapy and anti-PD-L1 therapy in NSCLC. METHODS: The role of the phosphoinositide 3-kinase/protein kinase B signal transducer and activator of transcription 3, epithelial-mesenchymal transition, and tripartite motif containing 21 in regulating PD-L1 expression after radiotherapy was investigated by small interfering-PD-L1-RNA transfection, immunohistochemistry, Western blot, and immunoprecipitation. The synergistic effect of radiotherapy and anti-PD-L1 antibody was evaluated in a mouse model. PD-L1 expression on tumor specimens was examined in a retrospective cohort of patients who received concurrent chemoradiotherapy. RESULTS: PD-L1 expression was increased in vivo and in vitro after conventionally fractionated radiation. Radiotherapy in combination with anti-PD-L1 antibody synergistically enhanced antitumor immunity by promoting CD8-positive T-cell infiltration and reducing the accumulation of myeloid-derived suppressor cells and tumor-infiltrating regulatory T cells in a mouse model. Radiotherapy may up-regulate PD-L1 expression through the phosphoinositide 3-kinase/AKT and signal transducer and activator of transcription 3 pathways. PD-L1 may also stimulate cell migration and facilitate the epithelial-mesenchymal transition process to induce radioresistance. Moreover, down-regulating PD-L1 could alleviate radioresistance by promoting apoptosis. Intriguingly, patients with negative PD-L1 expression had a significantly higher objective response rate (88% versus 43.1% [p < 0.001]) and disease control rate (100% versus 86.2% [p = 0.026]) than those with positive PD-L1 expression after delivery of radiotherapy. CONCLUSIONS: Conventionally fractionated radiotherapy in combination with anti-PD-L1 antibody shows a synergistic antitumor immunity in NSCLC. Furthermore, PD-L1 expression may be a significant clinical predictive factor for treatment response to radiotherapy in NSCLC.
INTRODUCTION: Immune escape frequently occurs and restricts the durability of the antitumor immune response to radiotherapy. Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) are important immune checkpoint molecules that could cause tumor cells to escape the host immune response. The aim of the study was to explore the role of PD-L1 in radioresistance and the antitumor effect of combined radiotherapy and anti-PD-L1 therapy in NSCLC. METHODS: The role of the phosphoinositide 3-kinase/protein kinase B signal transducer and activator of transcription 3, epithelial-mesenchymal transition, and tripartite motif containing 21 in regulating PD-L1 expression after radiotherapy was investigated by small interfering-PD-L1-RNA transfection, immunohistochemistry, Western blot, and immunoprecipitation. The synergistic effect of radiotherapy and anti-PD-L1 antibody was evaluated in a mouse model. PD-L1 expression on tumor specimens was examined in a retrospective cohort of patients who received concurrent chemoradiotherapy. RESULTS:PD-L1 expression was increased in vivo and in vitro after conventionally fractionated radiation. Radiotherapy in combination with anti-PD-L1 antibody synergistically enhanced antitumor immunity by promoting CD8-positive T-cell infiltration and reducing the accumulation of myeloid-derived suppressor cells and tumor-infiltrating regulatory T cells in a mouse model. Radiotherapy may up-regulate PD-L1 expression through the phosphoinositide 3-kinase/AKT and signal transducer and activator of transcription 3 pathways. PD-L1 may also stimulate cell migration and facilitate the epithelial-mesenchymal transition process to induce radioresistance. Moreover, down-regulating PD-L1 could alleviate radioresistance by promoting apoptosis. Intriguingly, patients with negative PD-L1 expression had a significantly higher objective response rate (88% versus 43.1% [p < 0.001]) and disease control rate (100% versus 86.2% [p = 0.026]) than those with positive PD-L1 expression after delivery of radiotherapy. CONCLUSIONS: Conventionally fractionated radiotherapy in combination with anti-PD-L1 antibody shows a synergistic antitumor immunity in NSCLC. Furthermore, PD-L1 expression may be a significant clinical predictive factor for treatment response to radiotherapy in NSCLC.
Authors: Salma K Jabbour; Abigail T Berman; Roy H Decker; Yong Lin; Steven J Feigenberg; Scott N Gettinger; Charu Aggarwal; Corey J Langer; Charles B Simone; Jeffrey D Bradley; Joseph Aisner; Jyoti Malhotra Journal: JAMA Oncol Date: 2020-06-01 Impact factor: 31.777