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

2019; Springer Nature; Volume: 39; Issue: 1 Linguagem: Inglês

10.1038/s41388-019-0971-7

1476-5594

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

Immunotherapy and Immune Responses

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.