Autophagy creates a CTL epitope that mimics tumor-associated antigens.
The detailed mechanisms responsible for processing tumor-associated antigens and presenting them to CTLs remain to be fully elucidated. In this study, we demonstrate a unique CTL epitope generated from the ubiquitous protein puromycin-sensitive aminopeptidase, which is presented via HLA-A24 on leukemic and pancreatic cancer cells but not on normal fibroblasts or EBV-transformed B lymphoblastoid cells. The generation of this epitope requires proteasomal digestion and transportation from the endoplasmic reticulum to the Golgi apparatus and is sensitive to chloroquine-induced inhibition of acidification inside the endosome/lysosome. Epitope liberation depends on constitutively active autophagy, as confirmed with immunocytochemistry for the autophagosome marker LC3 as well as RNA interference targeting two different autophagy-related genes. Therefore, ubiquitously expressed proteins may be sources of specific tumor-associated antigens when processed through a unique mechanism involving autophagy.
Division of Immunology, Aichi Cancer Center Research Institute, Nagoya, Japan. ademachi@aichi-cc.jp
Ayako
A
Demachi-Okamura
Hiroki
H
Torikai
Yoshiki
Y
Akatsuka
Hiroyuki
H
Miyoshi
Tamotsu
T
Yoshimori
Kiyotaka
K
Kuzushima
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000626:Aminopeptidases / Q000235:genetics / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology; D001343:Autophagy / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D000939:Epitopes / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D005347:Fibroblasts / Q000276:immunology; D059871:HLA-A24 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007938:Leukemia / Q000276:immunology / Q000473:pathology; D018716:Molecular Mimicry; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology; D034622:RNA Interference; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014617:Vacuoles / Q000378:metabolism
D000951:Antigens, Neoplasm; D000939:Epitopes; D059871:HLA-A24 Antigen; D011994:Recombinant Proteins; C067713:lactacystin; D000626:Aminopeptidases; C025579:enkephalin degrading enzyme; D000111:Acetylcysteine