Anti‐PD‐L1 Antibody Enhances T Cell Immune Responses and Reduces Resistance of Breast Cancer Cells to Radiotherapy
Leiming Guo, Gaofeng Ding, Wencai Xu, Hong Ge, Yue Jiang, Yufei Lu
Abstract
Immune escape is a frequent occurrence, which limits the duration of antitumor immune responses to radiotherapy. Here, we aimed to ascertain the roles and underlying mechanisms of programmed death ligand 1 (PD‐L1) in tolerance of breast cancer (BC) to radiotherapy. We first quantified microRNA‐21 (miR‐21) and PD‐L1 expression in BC tissues and cells, followed by identification of the interactions between miR‐21, PD‐L1, and programmed cell death protein 4 (PDCD4). miR‐21 knock‐in mice were used to construct tumor‐bearing models, which were then treated with anti‐PD‐L1 antibody and irradiation, followed by measurement of tumor growth and tumor immune escape. Finally, we evaluated the synergistic effects of radiotherapy and anti‐PD‐L1 antibody in vivo. The results showed increased miR‐21 expression in BC tissues and cells, which was positively correlated with PD‐L1 expression. The treatment with radiotherapy or anti‐PD‐L1 antibody in the miR‐21 knock‐in mice diminished tumor weight and volume, along with decreased CD3 + CD8 + positive cells, serum IL‐2 and IFN‐ γ levels, and lower PD‐L1 expression, but augmented apoptosis of T and BC cells. Moreover, miR‐21 significantly augmented PD‐L1 expression via PI3K/Akt pathway activation by targeting PDCD4 in BC cells. Thus, radiotherapy and anti‐PD‐L1 antibody synergistically accelerated the therapeutic effect against BC in mice, thereby implicating a close interplay between radiotherapy, T cells, and the miR‐21/PDCD4/PI3K/Akt/PD‐L1 axis.