title: Type I interferons induced by radiation therapy mediate recruitment and effector function of CD8(+) T cells.
abstract: The need for an intact immune system for cancer radiation therapy to be effective suggests that radiation not only acts directly on the tumor but also indirectly, through the activation of host immune components. Recent studies demonstrated that endogenous type I interferons (type I IFNs) play a role in radiation-mediated anti-tumor immunity by enhancing the ability of dendritic cells to cross-prime CD8(+) T cells. However, it is still unclear to what extent endogenous type I IFNs contribute to the recruitment and function of CD8(+) T cells. Little is also known about the effects of type I IFNs on myeloid cells. In the current study, we demonstrate that type I and type II IFNs (IFN-γ) are both required for the increased production of CXCL10 (IP-10) chemokine by myeloid cells within the tumor after radiation treatment. Radiation-induced intratumoral IP-10 levels in turn correlate with tumor-infiltrating CD8(+) T cell numbers. Moreover, type I IFNs promote potent tumor-reactive CD8(+) T cells by directly affecting the phenotype, effector molecule production, and enhancing cytolytic activity. Using a unique inducible expression system to increase local levels of IFN-α exogenously, we show here that the capacity of radiation therapy to result in tumor control can be enhanced. Our preclinical approach to study the effects of local increase in IFN-α levels can be used to further optimize the combination therapy strategy in terms of dosing and scheduling, which may lead to better clinical outcome.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester, Rochester, 601 Elmwood Ave, Box 672, Rochester, NY, 14642, USA.
authors.forename: Joanne Y H
authors.initials: JY
authors.lastname: Lim
authors.forename: Scott A
authors.initials: SA
authors.lastname: Gerber
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Murphy
authors.forename: Edith M
authors.initials: EM
authors.lastname: Lord
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000528:radiation effects*; D002465:Cell Movement / Q000528:radiation effects; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018655:Lymphocyte Count; D015674:Mammary Neoplasms, Animal / Q000276:immunology / Q000532:radiotherapy*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000532:radiotherapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D009368:Neoplasm Transplantation
chemical_list: D000951:Antigens, Neoplasm; D054357:Chemokine CXCL10; D016898:Interferon-alpha; D007371:Interferon-gamma