Non-canonical autophagy in dendritic cells restricts cross-presentation and anti-tumor immunity

Abstract

41Major Histocompatibility Complex I (MHC-I) molecules classically present peptides derived from 42 endogenous antigens, but exogenous antigens can also gain access to the MHC-I machinery in 43 dendritic cells (DCs), which can activate antigen-specific CD8 + T cells. This process, termed 44 cross-presentation, can be triggered by the uptake of dying autologous cells, including tumor cells, 45by DCs. The molecular mechanisms that underlie efficient cross-presentation remain largely 46 uncharacterized, and an improved understanding of these mechanisms might reveal novel 47 strategies for anti-tumor therapies. Rubicon (RUBCN) is a molecule required for LC3-associated 48 phagocytosis (LAP), but dispensable for canonical autophagy, and mice lacking this protein 49 develop an autoimmune inflammatory pathology with age. Here, we demonstrate that Rubcn-50 deficient DCs have increased retention of engulfed cellular cargo in immature phagosomes 51 resulting in increased phagosome-to-cytosol escape and antigen access to proteasome-mediated 52 degradation. As a result, mice selectively lacking Rubcn in DCs mount stronger tumor antigen-53 specific CD8 + T cell responses and exhibit decreased tumor burden compared to wild type 54 littermates. These findings identify LAP as a key regulator of cross-presentation and suggest that 55 targeting RUBCN might represent a novel strategy for anti-tumor therapy.The ability of the immune system to distinguish between self and non-self is integral to maintaining 75 homeostasis and eradicating exogenous threats. Antigen-presenting cells (APCs), specifically 76 DCs, educate the host's adaptive immune response in a controlled and antigen-specific manner. 77CD8 + T cells are activated by peptides generated from intracellular antigens and presented in the 78 context of MHC-I. Peptides derived from healthy self-antigens presented to CD8 + T cells in the 79 periphery elicit a minimal or absent response, as CD8 + T cells expressing T cell receptors (TCRs) 80 that recognize self-antigens undergo negative selection in the thymus prior to their population of 81 the periphery (Rock et al., 2016). However, when cells are infected by virus or are transformed 82 by an oncogene, they can produce proteins that are not considered self, such as virus-encoded 83 proteins, and the presentation of these aberrant antigens via MHC-I activates a robust CD8 + T 84 cell response (Hansen and Bouvier, 2009). Therefore, the MHC-I pathway represents an 85 evolutionarily conserved mechanism that serves as a quality control mechanism for endogenous 86 proteins and viral defense (Kaufman, 2018). 88As the activation of CD8 + T cells is largely limited to their localization within secondary lymphoid 89 tissues, they must rely on the migration of patrolling APCs to deliver antigens to them (Hansen 90 and Bouvier, 2009). Classically, exogenous antigens are sensed as foreign, phagocytosed, 91 processed by the endosomal-lysosomal network, and loaded onto MHC-II molecules to stimulate 92 antigen-specific activation of CD4 + T cel...

Recent Advances in Nanotechnology for Dendritic Cell-Based Immunotherapy

“…Nanotechnology-enabled spatiotemporal delivery of formulations aimed to directly activate DCs has been demonstrated in numerous cases ( Figure 2 ). These formulations can be classified into three categories: (1) those that target and activate local DC response in the tumor microenvironment in addition to chemotherapy/radiotherapy ( Sau et al., 2018 ); (2) those that target and activate lymph node-resident DCs, and in addition, target activation receptors on DCs, thereby boosting specific T cell response ( De Koker et al., 2016 ; Jiang et al., 2017 ); and (3) those that modulate intracellular antigen presentation process for higher cross-presentation efficacy ( Sil et al., 2019 ; Wang et al., 2019a ).…”