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

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.

Keywords: Myeloid-derived suppressor cells; PI3K/AKT pathway; Programmed death ligand 1; Radiation resistance; Tumor-infiltrating regulatory T cells.