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 and Amato J. Giaccia ()
Additional contact information
Todd A. Aguilera: 269 Campus Drive, Stanford University
Marjan Rafat: 269 Campus Drive, Stanford University
Laura Castellini: 269 Campus Drive, Stanford University
Hussein Shehade: 269 Campus Drive, Stanford University
Mihalis S. Kariolis: 269 Campus Drive, Stanford University
Angela Bik-Yu Hui: Stanford Cancer Institute
Henning Stehr: 269 Campus Drive, Stanford University
Rie von Eyben: 269 Campus Drive, Stanford University
Dadi Jiang: 269 Campus Drive, Stanford University
Lesley G. Ellies: University of California San Diego
Albert C. Koong: 269 Campus Drive, Stanford University
Maximilian Diehn: 269 Campus Drive, Stanford University
Erinn B. Rankin: 269 Campus Drive, Stanford University
Edward E. Graves: 269 Campus Drive, Stanford University
Amato J. Giaccia: 269 Campus Drive, Stanford University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13898

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