Genetic regulation of the response to Her-2 DNA vaccination in human Her-2 transgenic mice.
Genetic regulation of immune reactivity to Her-2 vaccination and the consequent antitumor effect was tested in human Her-2 transgenic (Tg) mice of C57BL/6 (B6), BALB/c (BALB), and (B6x BALB) F1 (F1) background. Mice were electrovaccinated with Her-2 DNA with or without pretreatment with CD25 monoclonal antibody to remove CD25(hi) regulatory T cells. When CD25(+) T cells were intact, BALB Her-2 Tg mice were more responsive than the other two strains in both humoral and cellular immunities, and their tumor growth was significantly delayed. B6 Her-2 Tg mice responded poorly and F1 mice showed modest immune reactivity, but tumor growth did not change in either strain. Depletion of CD25(hi) T cells before vaccination significantly improved protection from tumor challenge in F1 Her-2 Tg mice. This was associated with elevated levels of Her-2 IgG1, IgG2a, and IgG2c antibodies, and some mice also showed IFN-gamma producing T-cell response. The same treatment induced modest improvement in B6 Her-2 Tg mice. In BALB Her-2 Tg mice, however, depletion of CD25(hi) T cells did not further improve antitumor efficacy. Although their Her-2-specific IgG1 and interleukin-5-secreting T cells increased, the levels of IgG2a and IFN-gamma-secreting T cells did not change. These results are the first to show genetic regulation of the response to a cancer vaccine and an unequal effect of removing CD25(hi) T cells on antitumor immunity. These results warrant individualized treatment plans for patients with heterogeneous genetic backgrounds and possibly differential intrinsic immune reactivity to tumor antigens.
Radkevich-Brown
Olga
O
Karmanos Cancer Institute, Wayne State University, 110 E. Warren Avenue, Detroit, MI 48201, USA.
Jacob
Jennifer
J
Kershaw
Michael
M
Wei
Wei-Zen
WZ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D019496:Cancer Vaccines / Q000235:genetics* / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008213:Lymphocyte Activation; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D019444:Vaccines, DNA / Q000235:genetics* / Q000276:immunology*
D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D053645:Interleukin-2 Receptor alpha Subunit; D018719:Erb-b2 Receptor Tyrosine Kinases; D019444:Vaccines, DNA