title: Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity.
abstract: Alterations to the tumor microenvironment following localized irradiation may influence the effectiveness of subsequent immunotherapy. The objective of this study was to determine how IFN-gamma influences the inflammatory response within this dynamic environment following radiotherapy. B16/OVA melanoma cells were implanted into C57BL/6 (wild-type (WT)) and IFN-gamma-deficient (IFN-gamma-/-) mice. Seven days after implantation, mice received 15 Gy of localized tumor irradiation and were assessed 7 days later. Irradiation up-regulated the expression of VCAM-1 on the vasculature of tumors grown in WT but not in IFN-gamma-/- mice. Levels of the IFN-gamma-inducible chemokines MIG and IFN-gamma-inducible protein 10 were decreased in irradiated tumors from IFN-gamma-/- mice compared with WT. In addition to inducing molecular cues necessary for T cell infiltration, surface MHC class I expression is also up-regulated in response to IFN-gamma produced after irradiation. The role of IFN-gamma signaling in tumor cells on class I expression was tested using B16/OVA cells engineered to overexpress a dominant negative mutant IFN-gamma receptor (B16/OVA/DNM). Following implantation and treatment, expression of surface class I on tumor cells in vivo was increased in B16/OVA, but not in B16/OVA/DNM tumors, suggesting IFN-gamma acts directly on tumor cells to induce class I up-regulation. These increases in MHC class I expression correlated with greater levels of activated STAT1. Thus, IFN-gamma is instrumental in creating a tumor microenvironment conducive for T cell infiltration and tumor cell target recognition.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Amit A
authors.initials: AA
authors.lastname: Lugade
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Sorensen
authors.forename: Scott A
authors.initials: SA
authors.lastname: Gerber
authors.forename: James P
authors.initials: JP
authors.lastname: Moran
authors.forename: John G
authors.initials: JG
authors.lastname: Frelinger
authors.forename: Edith M
authors.initials: EM
authors.lastname: Lord
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology / Q000528:radiation effects; D005720:Gamma Rays; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics / Q000528:radiation effects; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000172:deficiency / Q000502:physiology / Q000528:radiation effects*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology / Q000528:radiation effects; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology / Q000528:radiation effects; D015854:Up-Regulation / Q000276:immunology / Q000528:radiation effects
chemical_list: D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma