ABSTRACT
Radiotherapy induces immune-related responses in cancer patients by various mechanisms. Here, we investigate the immunomodulatory role of tumor-derived microparticles (TMPs)-extracellular vesicles shed from tumor cells-following radiotherapy. We demonstrate that breast carcinoma cells exposed to radiation shed TMPs containing elevated levels of immune-modulating proteins, one of which is programmed death-ligand 1 (PD-L1). These TMPs inhibit cytotoxic T lymphocyte (CTL) activity both in vitro and in vivo, and thus promote tumor growth. Evidently, adoptive transfer of CTLs pre-cultured with TMPs from irradiated breast carcinoma cells increases tumor growth rates in mice recipients in comparison with control mice receiving CTLs pre-cultured with TMPs from untreated tumor cells. In addition, blocking the PD-1-PD-L1 axis, either genetically or pharmacologically, partially alleviates TMP-mediated inhibition of CTL activity, suggesting that the immunomodulatory effects of TMPs in response to radiotherapy is mediated, in part, by PD-L1. Overall, our findings provide mechanistic insights into the tumor immune surveillance state in response to radiotherapy and suggest a therapeutic synergy between radiotherapy and immune checkpoint inhibitors.
Subject(s)
B7-H1 Antigen/genetics , Breast Neoplasms/radiotherapy , Cell-Derived Microparticles/immunology , Immunomodulation/immunology , Animals , B7-H1 Antigen/immunology , Breast Neoplasms/genetics , Breast Neoplasms/immunology , Cell Line, Tumor , Cell-Derived Microparticles/genetics , Cell-Derived Microparticles/radiation effects , Female , Heterografts , Humans , Immune Evasion/immunology , Immune Evasion/radiation effects , Immunomodulation/radiation effects , Mice , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology , Signal Transduction/radiation effects , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/radiation effectsABSTRACT
BACKGROUND: In the present study, we aimed to investigate the role of epidermal growth factor receptor (EGFR) pathway in the up-regulation of programmed death ligand-1 (PD-L1) caused by radiotherapy (RT). MATERIALS AND METHODS: Tissue microarrays (TMA) consisting of glioma cancer specimens from 64 patients were used to examine the correlation between PD-L1 and EGFR levels. Furthermore, we performed in vitro experiments to assess the role of EGFR pathway in RT-upregulated PD-L1 expression using human glioma cell lines U87 and U251. RESULTS: Our data demonstrated that the PD-L1 expression was significantly correlated with EGFR expression in glioma specimens (χ2=5.00, P=0.025). The expressions of PD-L1 at the protein and mRNA levels were both significantly up-regulated by RT (P<0.05). The expressions of phosphorylated EGFR and janus kinase 2 (JAK2) were also induced by RT (P<0.05). Besides, inhibition of EGFR pathway could abrogate the RT-triggered PD-L1 up-regulation (P>0.05). The combination of RT with EGFR inhibitor exhibited the same effect on antitumor immune response compared with the combination of RT with PD-L1 neutralizing antibody (Ab). CONCLUSIONS: RT could up-regulate the PD-L1 expression through the pathways downstream of EGFR in glioma.
