Reprogramming the immunological microenvironment through radiation and targeting Axl

Todd A. Aguilera, Marjan Rafat, Laura Castellini, Hussein Shehade, Mihalis S. Kariolis, Angela Bik Yu Hui, Henning Stehr, Rie Von Eyben, Dadi Jiang, Lesley G. Ellies, Albert C. Koong, Maximilian Diehn, Erinn B. Rankin, Edward E. Graves, Amato J. Giaccia

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Abstract

Increasing evidence suggests that ionizing radiation therapy (RT) in combination with checkpoint immunotherapy is highly effective in treating a subset of cancers. To better understand the limited responses to this combination we analysed the genetic, microenvironmental, and immune factors in tumours derived from a transgenic breast cancer model. We identified two tumours with similar growth characteristics but different RT responses primarily due to an antitumour immune response. The combination of RT and checkpoint immunotherapy resulted in cures in the responsive but not the unresponsive tumours. Profiling the tumours revealed that the Axl receptor tyrosine kinase is overexpressed in the unresponsive tumours, and Axl knockout resulted in slower growth and increased radiosensitivity. These changes were associated with a CD8 + T-cell response, which was improved in combination with checkpoint immunotherapy. These results suggest a novel role for Axl in suppressing antigen presentation through MHCI, and enhancing cytokine release, which promotes a suppressive myeloid microenvironment.

Original languageEnglish (US)
Article number13898
JournalNature Communications
Volume7
DOIs
StatePublished - Dec 23 2016

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Aguilera, T. A., Rafat, M., Castellini, L., Shehade, H., Kariolis, M. S., Hui, A. B. Y., Stehr, H., Von Eyben, R., Jiang, D., Ellies, L. G., Koong, A. C., Diehn, M., Rankin, E. B., Graves, E. E., & Giaccia, A. J. (2016). Reprogramming the immunological microenvironment through radiation and targeting Axl. Nature Communications, 7, [13898]. https://doi.org/10.1038/ncomms13898