Journal Article

Microparticles from tumors exposed to radiation promote immune evasion in part by PD-L1

Kotsofruk, Ruslana, Magidey, Ksenia, Shechter, Dvir, Elisabeth G E de Vries, Kaidar-Person, Orit, Nevelsky, Alexander, Timaner, Michael, Zhang, Tongwu, Kerbel, Robert S, Shaked, Yuval, Kan, Tal, Shahar, Daniel, Raviv, Ziv

2020

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Adoptive transfer / Apoptosis / Breast cancer / Breast carcinoma / Cytotoxicity / Extracellular vesicles / Growth rate / Immune checkpoint inhibitors / Immune evasion / Immunomodulation / Immunomodulators / Immunosurveillance / Lymphocytes T / Microparticles / PD-1 protein / PD-L1 protein / Radiation therapy / Tumor cells / Tumors