title: The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity.
abstract: The most widely held explanation for the efficacy of local radiotherapy (RT) is based on direct cytotoxicity to cancer cells through the induction of lethal DNA damage. Recent studies have shown that local ablative radiation of established tumors can lead to increased T-cell priming and T-cell-dependent tumor regression, but the underlying mechanism remains unclear. Here, we describe an essential role for type I IFN in local RT-mediated tumor control. We show that ablative RT increases intratumoral production of IFN-β and, more surprisingly, the antitumor effect of RT is abolished in type I IFN nonresponsive hosts. Furthermore, the major target of RT-induced type I IFN is the hematopoietic compartment. RT drastically enhances the cross-priming capacity of tumor-infiltrating dendritic cells (TIDC) from wild-type mice but not type I IFN receptor-deficient mice. The enhanced cross-priming ability of TIDCs after RT was dependent on autocrine production of type I IFNs. By using adenoviral-mediated expression of IFN-β, we show that delivery of exogenous IFN-β into the tumor tissue in the absence of RT is also sufficient to selectively expand antigen-specific T cells leading to complete tumor regression. Our study reveals that local high-dose RT can trigger production of type I IFN that initiates a cascading innate and adaptive immune attack on the tumor.
authors.affiliation: Departments of Pathology and Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, University of Chicago, Chicago, Illinois, USA.
authors.forename: Byron C
authors.initials: BC
authors.lastname: Burnette
authors.forename: Hua
authors.initials: H
authors.lastname: Liang
authors.forename: Youjin
authors.initials: Y
authors.lastname: Lee
authors.forename: Lukasz
authors.initials: L
authors.lastname: Chlewicki
authors.forename: Nikolai N
authors.initials: NN
authors.lastname: Khodarev
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
authors.forename: Sogyong L
authors.initials: SL
authors.lastname: Auh
mesh_terms: D056704:Adaptive Immunity / Q000528:radiation effects; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000528:radiation effects; D003713:Dendritic Cells / Q000276:immunology / Q000528:radiation effects; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000528:radiation effects; D007113:Immunity, Innate / Q000528:radiation effects; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D016898:Interferon-alpha / Q000096:biosynthesis / Q000276:immunology; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000532:radiotherapy*; D051379:Mice; D018345:Mice, Knockout; D059016:Tumor Microenvironment / Q000276:immunology / Q000528:radiation effects
chemical_list: D018984:Epitopes, T-Lymphocyte; D007370:Interferon Type I; D016898:Interferon-alpha; D016899:Interferon-beta