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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)187-203
Number of pages17
JournalOncogene
Volume39
Issue number1
DOIs
StatePublished - 2 Jan 2020
Externally publishedYes

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