title: Tumor-derived autophagosome vaccine: mechanism of cross-presentation and therapeutic efficacy.
abstract: OBJECTIVE
  We previously reported that autophagy in tumor cells plays a critical role in cross-presentation of tumor antigens and that autophagosomes are efficient antigen carriers for cross-priming of tumor-reactive CD8(+) T cells. Here, we sought to characterize further the autophagosome-enriched vaccine named DRibble (DRiPs-containing blebs), which is derived from tumor cells after inhibition of protein degradation, and to provide insights into the mechanisms responsible for their efficacy as a novel cancer immunotherapy.
  
  
  METHODS
  DRibbles were characterized by Western blot and light or transmission electron microscopy. The efficiency of cross-presentation mediated by DRibbles was first compared with that of whole-tumor cells and pure proteins. The mechanisms of antigen cross-presentation by DRibbles were analyzed, and the antitumor efficacy of the DRibble vaccine was tested in 3LL Lewis lung tumors and B16F10 melanoma.
  
  
  RESULTS
  The DRibbles sequester both long-lived and short-lived proteins, including defective ribosomal products (DRiP), and damage-associated molecular pattern molecules exemplified by HSP90, HSP94, calreticulin, and HMGB1. DRibbles express ligands for CLEC9A, a newly described C-type lectin receptor expressed by a subset of conventional and plasmacytoid dendritic cells (DC), and cross-presentation was partially CLEC9A dependent. Furthermore, this autophagy-assisted antigen cross-presentation pathway involved both caveolae- and clathrin-mediated endocytosis and endoplasmic reticulum-associated degradation machinery. It depends on proteasome and TAP1, but not lysosome functions of antigen-presenting cells. Importantly, DCs loaded with autophagosome-enriched DRibbles can eradicate 3LL Lewis lung tumors and significantly delay the growth of B16F10 melanoma.
  
  
  CONCLUSIONS
  These data documented the unique characteristics and potent antitumor efficacy of the autophagosome-based DRibble vaccine. The efficacy of DRibble cancer vaccine will be further tested in clinical trials.
authors: Laboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon 97213, USA.
authors: Yuhuan
authors: Y
authors: Li
authors: Li-Xin
authors: LX
authors: Wang
authors: Puiyi
authors: P
authors: Pang
authors: Zhihua
authors: Z
authors: Cui
authors: Sandra
authors: S
authors: Aung
authors: Daniel
authors: D
authors: Haley
authors: Bernard A
authors: BA
authors: Fox
authors: Walter J
authors: WJ
authors: Urba
authors: Hong-Ming
authors: HM
authors: Hu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000628:therapy*; D045744:Cell Line, Tumor; D045142:Cross-Priming; D055612:Cytokine-Induced Killer Cells; D006801:Humans; D008546:Melanoma, Experimental / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D019496:Cancer Vaccines