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

Timaner, M., Kotsofruk, R., Raviv, Z., Magidey, K., Shechter, D., Kan, T., Nevelsky, A., Daniel, S., de Vries, E. G. E., Zhang, T., Kaidar-Person, O., Kerbel, R. S. & Shaked, Y., Jan-2020, In : ONCOGENE. 39, 1, p. 187-203 17 p.

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DOI

  • 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

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
Publication statusPublished - Jan-2020

    Keywords

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

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