Antigen-specific CD8+ T lymphocytes generated from a DNA vaccine control tumors through the Fas-FasL pathway.
Human papillomavirus, particularly type 16, and its oncogenic proteins, E6 and E7, are consistently expressed in most cervical cancers. One of the major issues facing cancer immunotherapy is that many human cancers evade the immune system by downregulating the expression of Fas molecules. An E7-expressing murine tumor model with a downregulated Fas expression--TC-1 P3(A15) tumors--was created. A DNA vaccine encoding calreticulin linked to E7 (CRT/E7) was able to generate protective and therapeutic antitumor effects against TC-1 P3(A15) tumors. In vitro Ab depletion and in vivo adoptive experiments showed that the antitumor effect of E7-specific CD8+ T lymphocytes against the TC-1 P3(A15) tumor cells was through the Fas-FasL-dependent CTL effector mechanism, and the TC-1 P3(A15) tumor cells needed higher numbers of antigen-specific CD8+ T lymphocytes for in vivo elimination. Our results demonstrated that chimeric CRT/E7 DNA vaccine resulted in control of tumors with downregulated Fas expression, highlighting the importance of the Fas-FasL pathway in the potent antitumor effect of antigen-specific CD8+ cytotoxic T lymphocytes and the role of Fas as part of in vivo tumor evasion.
Cheng
Wen-Fang
WF
Department of Obstetrics and Gynecology, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.
Lee
Chien-Nan
CN
Chang
Ming-Cheng
MC
Su
Yi-Ning
YN
Chen
Chi-An
CA
Hsieh
Chang-Yao
CY
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D015536:Down-Regulation; D053222:Fas Ligand Protein; D005260:Female; D015316:Genetic Therapy; D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000096:biosynthesis*; D019444:Vaccines, DNA; D019014:fas Receptor / Q000378:metabolism*
D019496:Cancer Vaccines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors; D019444:Vaccines, DNA; D019014:fas Receptor; D007371:Interferon-gamma