PT  - JOURNAL ARTICLE
AU  - Payel Sil
AU  - Fei Zhao
AU  - Ginger W. Muse
AU  - Sing-Wai Wong
AU  - Joseph P. Kolb
AU  - Laura Miller DeGraff
AU  - Charles J. Tucker
AU  - Erica Scappini
AU  - Annelise G. Snyder
AU  - Sara Grimm
AU  - Andrew Oberst
AU  - Jennifer Martinez
TI  - Non-canonical autophagy in dendritic cells restricts cross-presentation and anti-tumor immunity
AID  - 10.1101/789867
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 789867
4099  - http://biorxiv.org/content/early/2019/10/02/789867.short
4100  - http://biorxiv.org/content/early/2019/10/02/789867.full
AB  - Major 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 that Rubcn-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 lacking Rubcn in 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.