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.
Nowak
Anna K
AK
Tumor Immunology Group, Department of Medicine, University of Western Australia and Western Australian Institute of Medical Research, Perth, Australia.
Lake
Richard A
RA
Marzo
Amanda L
AL
Scott
Bernadette
B
Heath
William R
WR
Collins
Edward J
EJ
Frelinger
Jeffrey A
JA
Robinson
Bruce W S
BW
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