Reprogramming the immunological microenvironment through radiation and targeting Axl.

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 13898 (12 23 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 28008921 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Histocompatibility Antigens Class I
• Proto-Oncogene Proteins
• Receptor Protein-Tyrosine Kinases
• Axl Receptor Tyrosine Kinase
• AXL receptor tyrosine kinase, mouse

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Combined Modality Therapy
• Cytokines (metabolism)
• Histocompatibility Antigens Class I (metabolism)
• Immunity
• Immunosuppression Therapy
• Immunotherapy
• Mice, Inbred C57BL
• Mice, Transgenic
• Models, Biological
• Molecular Targeted Therapy
• Neoplasms (enzymology, immunology)
• Proto-Oncogene Proteins (metabolism)
• Radiation Tolerance (radiation effects)
• Receptor Protein-Tyrosine Kinases (metabolism)
• Tumor Microenvironment (immunology, radiation effects)
• Axl Receptor Tyrosine Kinase