Type I interferon is selectively required by dendritic cells for immune rejection of tumors
Mark S Diamond, Michelle Kinder, Hirokazu Matsushita, Mona Mashayekhi, Gavin P Dunn, Jessica M Archambault, Hsiaoju Lee, Cora D Arthur, J Michael White, Ulrich Kalinke, Kenneth M Murphy, Robert D Schreiber, Mark S Diamond, Michelle Kinder, Hirokazu Matsushita, Mona Mashayekhi, Gavin P Dunn, Jessica M Archambault, Hsiaoju Lee, Cora D Arthur, J Michael White, Ulrich Kalinke, Kenneth M Murphy, Robert D Schreiber
Abstract
Cancer immunoediting is the process whereby the immune system suppresses neoplastic growth and shapes tumor immunogenicity. We previously reported that type I interferon (IFN-α/β) plays a central role in this process and that hematopoietic cells represent critical targets of type I IFN's actions. However, the specific cells affected by IFN-α/β and the functional processes that type I IFN induces remain undefined. Herein, we show that type I IFN is required to initiate the antitumor response and that its actions are temporally distinct from IFN-γ during cancer immunoediting. Using mixed bone marrow chimeric mice, we demonstrate that type I IFN sensitivity selectively within the innate immune compartment is essential for tumor-specific T cell priming and tumor elimination. We further show that mice lacking IFNAR1 (IFN-α/β receptor 1) in dendritic cells (DCs; Itgax-Cre(+)Ifnar1(f/f) mice) cannot reject highly immunogenic tumor cells and that CD8α(+) DCs from these mice display defects in antigen cross-presentation to CD8(+) T cells. In contrast, mice depleted of NK cells or mice that lack IFNAR1 in granulocytes and macrophage populations reject these tumors normally. Thus, DCs and specifically CD8α(+) DCs are functionally relevant targets of endogenous type I IFN during lymphocyte-mediated tumor rejection.
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References
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