Author:
Sil Payel,Zhao Fei,Muse Ginger W.,Wong Sing-Wai,Kolb Joseph P.,DeGraff Laura Miller,Tucker Charles J.,Scappini Erica,Snyder Annelise G.,Grimm Sara,Oberst Andrew,Martinez Jennifer
Abstract
SummaryMajor Histocompatibility Complex I (MHC-I) molecules classically present peptides derived from endogenous antigens, but exogenous antigens can also gain access to the MHC-I machinery in dendritic cells (DCs), which can activate antigen-specific CD8+T cells. This process, termed cross-presentation, can be triggered by the uptake of dying autologous cells, including tumor cells, by DCs. The molecular mechanisms that underlie efficient cross-presentation remain largely uncharacterized, and an improved understanding of these mechanisms might reveal novel strategies for anti-tumor therapies. Rubicon (RUBCN) is a molecule required for LC3-associated phagocytosis (LAP), but dispensable for canonical autophagy, and mice lacking this protein develop an autoimmune inflammatory pathology with age. Here, we demonstrate thatRubcn-deficient DCs have increased retention of engulfed cellular cargo in immature phagosomes resulting in increased phagosome-to-cytosol escape and antigen access to proteasome-mediated degradation. As a result, mice selectively lackingRubcnin DCs mount stronger tumor antigen-specific CD8+T cell responses and exhibit decreased tumor burden compared to wild type littermates. These findings identify LAP as a key regulator of cross-presentation and suggest that targeting RUBCN might represent a novel strategy for anti-tumor therapy.
Publisher
Cold Spring Harbor Laboratory
Cited by
2 articles.
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