Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells.
Cross-presentation of cell-bound Ags from established, solid tumors to CD8 cells is efficient and likely to have a role in determining host response to tumor. A number of investigators have predicted that when tumor Ags are derived from apoptotic cells either no response, due to Ag "sequestration," or CD8 cross-tolerance would ensue. Because the crucial issue of whether this happens in vivo has never been addressed, we induced apoptosis of established hemagglutinin (HA)-transfected AB1 tumors in BALB/c mice using the apoptosis-inducing reagent gemcitabine. This shrank the tumor by approximately 80%. This induction of apoptosis increased cross-presentation of HA to CD8 cells yet neither gross deletion nor functional tolerance of HA-specific CD8 cells were observed, based on tetramer analysis, proliferation of specific CD8 T cells, and in vivo CTL activity. Interestingly, apoptosis primed the host for a strong antitumor response to a second, virus-generated HA-specific signal in that administration of an HA-expressing virus after gemcitabine administration markedly decreased tumor growth compared with viral administration without gemcitabine. Thus tumor cell apoptosis in vivo neither sequesters tumor Ags nor cross-tolerizes tumor-specific CD8 cells. This observation has fundamental consequences for the development of tumor immunotherapy protocols and for understanding T cell reactivity to tumors and the in vivo immune responses to apoptotic cells.
Tumor Immunology Group, Department of Medicine, University of Western Australia and Western Australian Institute of Medical Research, Perth, Australia.
Anna K
AK
Nowak
Richard A
RA
Lake
Amanda L
AL
Marzo
Bernadette
B
Scott
William R
WR
Heath
Edward J
EJ
Collins
Jeffrey A
JA
Frelinger
Bruce W S
BW
Robinson
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D017635:Clonal Anergy / Q000187:drug effects / Q000276:immunology*; D017637:Clonal Deletion / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D006131:Growth Inhibitors / Q000008:administration & dosage; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology / Q000378:metabolism; D007114:Immunization; D007274:Injections, Intraperitoneal; D008654:Mesothelioma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*; D000093542:Gemcitabine
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D003841:Deoxycytidine; D000093542:Gemcitabine