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.
Highlights
Breast cancer (BC) is the most prevalent malignancy in female populations worldwide and accounts for a quarter of all cancers in women, causing around 500,000 deaths annually [1]
Expression of miR-21 Was Abundant in Patients with BC after Radiotherapy and Positively Correlated with programmed death ligand 1 (PD-L1) Expression
MiR-21 was evident as highly expressed in BC tissues in The Cancer Genome Atlas (TCGA) database (Figure 1(c))
Summary
Breast cancer (BC) is the most prevalent malignancy in female populations worldwide and accounts for a quarter of all cancers in women, causing around 500,000 deaths annually [1]. In spite of remarkable advancements in molecular targeted therapy [2], BC remains the predominant contributor to the cancer-related deaths in female populations [3]. Adjuvant whole breast radiotherapy is an important treatment modality in the early stage of BC, lowering the risk of local recurrence and death [4]. Overexpression of miR-21 reduces ovarian cancer cell apoptosis and promotes cell proliferation by decreasing phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and enhancing phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) activity [7]. High miR-21 expression is linked to lower overall survival time among patients with BC [9]. MiR-21 overexpression is linked to the onset of drug resistance in BC [10]
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