Therapeutic HER2/Neu DNA vaccine inhibits mouse tumor naturally overexpressing endogenous neu.
The therapeutic efficacy of HER2/c-erbB-2/neu DNA immunization on mouse tumor cells expressing exogenous human or rat p185neu but not on mouse tumor cells naturally expressing mouse p185neu has been demonstrated. We investigated the feasibility of using N-terminal rat neu DNA immunization on mouse tumor overexpressing endogenous p185neu and enhancing the therapeutic efficacy of this vaccine by fusion to various cytokine genes, including interleukin-2 (IL-2), interleukin-4 (IL-4), or granulocyte-macrophage colony-stimulating factor. In a therapeutic model, N'-neu-IL-2 DNA vaccine was significantly better than N'-neu DNA vaccine, and N'-neu DNA vaccine was significantly better than control DNA or N'-neu-IL-4 DNA vaccine. The therapeutic efficacy of DNA vaccines was correlated with tumor infiltration of CD8+ T cells. Depletion of CD8+ T cells completely abolished the therapeutic effects of N'-neu-IL-2 DNA vaccine and N'-neu DNA vaccine. Depletion of CD4+ T cells after tumor implantation had no influence on N'-neu-IL-2 DNA vaccine, but enhanced the therapeutic efficacy of N'-neu DNA vaccine. Our results demonstrate that rat N'-neu DNA vaccine has a therapeutic effect on established tumor through the CD8+ T-cell-dependent pathway. Depletion of CD4+ T cells or fusion to the IL-2 gene can thus further enhance the therapeutic effects of N'-neu DNA immunization on mouse tumor expressing endogenous p185neu.
Lin
Chi-Chen
CC
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Chou
Ching-Wen
CW
Shiau
Ai-Li
AL
Tu
Cheng-Fen
CF
Ko
Tai-Ming
TM
Chen
Yi-Ling
YL
Yang
Bei-Chang
BC
Tao
Mi-Hua
MH
Lai
Ming-Derg
MD
D000818:Animals; D000961:Antilymphocyte Serum / Q000276:immunology; D019677:Artificial Gene Fusion; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000235:genetics / Q000627:therapeutic use*; D017637:Clonal Deletion / Q000276:immunology; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018734:Genes, erbB-2 / Q000235:genetics*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D019444:Vaccines, DNA / Q000235:genetics / Q000627:therapeutic use
D000961:Antilymphocyte Serum; D019496:Cancer Vaccines; D016207:Cytokines; D007376:Interleukin-2; D015847:Interleukin-4; D018719:Erb-b2 Receptor Tyrosine Kinases; D019444:Vaccines, DNA