Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells.

Abstract

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.

• Authors: Anna K Nowak, Richard A Lake, Amanda L Marzo, Bernadette Scott, William R Heath, Edward J Collins, Jeffrey A Frelinger, Bruce W S Robinson
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 170 Issue 10 Pg. 4905-13 (May 15 2003) ISSN: 0022-1767 [Print] United States
• PMID: 12734333 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Epitopes, T-Lymphocyte
• Growth Inhibitors
• Hemagglutinin Glycoproteins, Influenza Virus
• Deoxycytidine
• Gemcitabine

Topics

• Animals
• Antigen Presentation (drug effects)
• Antigen-Presenting Cells (immunology, metabolism)
• Antigens, Neoplasm (immunology, metabolism)
• Apoptosis (drug effects, immunology)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Clonal Anergy (drug effects, immunology)
• Clonal Deletion (drug effects, immunology)
• Cytotoxicity, Immunologic (drug effects)
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Dose-Response Relationship, Immunologic
• Epitopes, T-Lymphocyte (immunology, metabolism)
• Growth Inhibitors (administration & dosage)
• Hemagglutinin Glycoproteins, Influenza Virus (immunology, metabolism)
• Immunization
• Injections, Intraperitoneal
• Mesothelioma (drug therapy, immunology, pathology, prevention & control)
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Tumor Cells, Cultured
• Up-Regulation (drug effects, immunology)
• Gemcitabine