title: 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.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, 269 Campus Drive, Stanford University, Stanford, California 94305, USA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Aguilera
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, 269 Campus Drive, Stanford University, Stanford, California 94305, USA.
authors.forename: Marjan
authors.initials: M
authors.lastname: Rafat
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, 269 Campus Drive, Stanford University, Stanford, California 94305, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Castellini
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, 269 Campus Drive, Stanford University, Stanford, California 94305, USA.
authors.forename: Hussein
authors.initials: H
authors.lastname: Shehade
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, 269 Campus Drive, Stanford University, Stanford, California 94305, USA.
authors.forename: Mihalis S
authors.initials: MS
authors.lastname: Kariolis
authors.affiliation: Stanford Cancer Institute, 265 Campus Drive, Ste G2103, Stanford, California 94305, USA.
authors.forename: Angela Bik-Yu
authors.initials: AB
authors.lastname: Hui
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, 269 Campus Drive, Stanford University, Stanford, California 94305, USA.
authors.forename: Henning
authors.initials: H
authors.lastname: Stehr
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, 269 Campus Drive, Stanford University, Stanford, California 94305, USA.
authors.forename: Rie
authors.initials: R
authors.lastname: von Eyben
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, 269 Campus Drive, Stanford University, Stanford, California 94305, USA.
authors.forename: Dadi
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Lesley G
authors.initials: LG
authors.lastname: Ellies
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, 269 Campus Drive, Stanford University, Stanford, California 94305, USA.|Stanford Cancer Institute, 265 Campus Drive, Ste G2103, Stanford, California 94305, USA.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Koong
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, 269 Campus Drive, Stanford University, Stanford, California 94305, USA.|Stanford Cancer Institute, 265 Campus Drive, Ste G2103, Stanford, California 94305, USA.
authors.forename: Maximilian
authors.identifier: 0000-0003-2032-0581
authors.initials: M
authors.lastname: Diehn
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, 269 Campus Drive, Stanford University, Stanford, California 94305, USA.|Stanford Cancer Institute, 265 Campus Drive, Ste G2103, Stanford, California 94305, USA.
authors.forename: Erinn B
authors.initials: EB
authors.lastname: Rankin
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, 269 Campus Drive, Stanford University, Stanford, California 94305, USA.|Stanford Cancer Institute, 265 Campus Drive, Ste G2103, Stanford, California 94305, USA.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Graves
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, 269 Campus Drive, Stanford University, Stanford, California 94305, USA.|Stanford Cancer Institute, 265 Campus Drive, Ste G2103, Stanford, California 94305, USA.
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D016207:Cytokines / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007109:Immunity; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011836:Radiation Tolerance / Q000528:radiation effects; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000276:immunology* / Q000528:radiation effects*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722290:AXL receptor tyrosine kinase, mouse