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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)
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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
Publication statusPublished - Jan-2020

Keywords

  • CANCER-THERAPY
  • RADIOTHERAPY
  • CELLS
  • MECHANISMS
  • EXPRESSION
  • MEDIATORS
  • RESPONSES
  • ASSAY
  • MICROENVIRONMENT
  • MICROVESICLES

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