Cross-presentation of tumor associated antigens through tumor-derived autophagosomes

Abstract

Cross-presentation of exogenous antigens by host professional antigen-presenting cells (APCs) plays a pivotal role in the initiation and development of T-cell immune responses to tumor-associated antigens, including self or mutated self-antigens derived from tumor cells, and foreign antigens derived from infectious agents. Cross-presentation requires multiple steps that involve the antigens' synthesis and compartmentalization in donor cells, packaging and delivery, and processing and presentation by MHC class I molecules on professional APCs. The intricate pathways that lead to protein degradation and the formation of MHC I-peptide complexes inside the APC are well documented for both soluble and particulate antigens. However, much less is known about how cross-presentation is regulated by the protein degradation pathways in antigen-donor cells (ADCs), including autophagy-mediated lysosomal proteolysis and proteasomal degradation. The exact nature or form of the antigens derived from donor cells at the time of delivery to the APC for cross-presentation is very controversial.

Figure 1. A working model of antigen accumulation inside autophagosomes with inhibition of both proteasomes and lysosomes

Under normal culture conditions, the majority of DRiPs and SLiPs are ubiquitinated and targeted to proteasomes for their degradation, while long-lived proteins are targeted by autophagy to lysosomes for disposal. When both proteasomes and lysosomes are inhibited, SLiPs, DRiPs and misfolded proteins accumulate and form protein aggregates (ALIS/aggresomes), which then induce autophagy via p62 and Atg8/LC3 interaction. Peptide intermediates bound on hsp90 are encapsulated into autophagasomes and serve as immunogenic substrates for cross-presentation.