Combined Radiotherapy and Anti-PD-L1 Antibody Synergistically Enhances Antitumor Effect in Non-Small Cell Lung Cancer

• Published in: Journal of thoracic oncology Vol. 12; no. 7; p. 1085
• Main Authors: Gong, Xiaomei, Li, Xuefei, Jiang, Tao, Xie, Huikang, Zhu, Zhengfei, Zhou, Fei, Zhou, Caicun
• Format: Journal Article
• Language: English
• Published: United States 01-07-2017
• Subjects: Animals; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - radiotherapy; Female; Humans; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lung Neoplasms - radiotherapy; Lymphocytes, Tumor-Infiltrating - immunology; Mice; Mice, Inbred C57BL; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Signal Transduction; Transfection; Radiation resistance; Programmed death ligand 1; Tumor-infiltrating regulatory T cells; Myeloid-derived suppressor cells; PI3K/AKT pathway
• ISSN: 1556-1380
• DOI: 10.1016/j.jtho.2017.04.014

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.
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.
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.
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.