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Radiation-Induced IFN- Production within the Tumor Microenvironment Influences Antitumor Immunity¹

Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642

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- influences the inflammatory response within this dynamic environment following radiotherapy. B16/OVA melanoma cells were implanted into C57BL/6 (wild-type (WT)) and IFN--deficient (IFN-^–/–) 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-^–/– mice. Levels of the IFN--inducible chemokines MIG and IFN--inducible protein 10 were decreased in irradiated tumors from IFN-^–/– 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- produced after irradiation. The role of IFN- signaling in tumor cells on class I expression was tested using B16/OVA cells engineered to overexpress a dominant negative mutant IFN- 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- 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- is instrumental in creating a tumor microenvironment conducive for T cell infiltration and tumor cell target recognition.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant CA28332 and by a grant from the Sally Edelman and Harry Gardner Cancer Research Foundation. A.A.L., S.A.G., and J.P.M. were supported by the National Institutes of Health Training Grant AI07285.

² Address correspondence and reprint requests to Dr. Edith M. Lord, Department of Microbiology and Immunology, Box 672, 601 Elmwood Avenue, Rochester, NY 14642. E-mail address: Edith_Lord{at}urmc.rochester.edu

³ Abbreviations used in this paper: IP-10, IFN--inducible protein 10; WT, wild type; TIL, tumor-infiltrating lymphocyte.