Elimination of IL-10-inducing T-helper epitopes from an IGFBP-2 vaccine ensures potent antitumor activity.
Immunization against self-tumor antigens can induce T-regulatory cells, which inhibit proliferation of type I CD4(+) T-helper (TH1) and CD8(+) cytotoxic T cells. Type I T cells are required for potent antitumor immunity. We questioned whether immunosuppressive epitopes could be identified and deleted from a cancer vaccine targeting insulin-like growth factor-binding protein (IGFBP-2) and enhance vaccine efficacy. Screening breast cancer patient lymphocytes with IFN-γ and interleukin (IL)-10 ELISPOT, we found epitopes in the N-terminus of IGFBP-2 that elicited predominantly TH1 whereas the C-terminus stimulated TH2 and mixed TH1/TH2 responses. Epitope-specific TH2 demonstrated a higher functional avidity for antigen than epitopes, which induced IFN-γ (P = 0.014). We immunized TgMMTV-neu mice with DNA constructs encoding IGFBP-2 N-and C-termini. T cell lines expanded from the C-terminus vaccinated animals secreted significantly more type II cytokines than those vaccinated with the N-terminus and could not control tumor growth when infused into tumor-bearing animals. In contrast, N-terminus epitope-specific T cells secreted TH1 cytokines and significantly inhibited tumor growth, as compared with naïve T cells, when adoptively transferred (P = 0.005). To determine whether removal of TH2-inducing epitopes had any effect on the vaccinated antitumor response, we immunized mice with the N-terminus, C-terminus, and a mix of equivalent concentrations of both vaccines. The N-terminus vaccine significantly inhibited tumor growth (P < 0.001) as compared with the C-terminus vaccine, which had no antitumor effect. Mixing the C-terminus with the N-terminus vaccine abrogated the antitumor response of the N-terminus vaccine alone. The clinical efficacy of cancer vaccines targeting self-tumor antigens may be greatly improved by identification and removal of immunosuppressive epitopes.
Authors' Affiliations: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Miami, Miami, Florida; and Division of Oncology/Hematology, Department of Internal Medicine, Korea University, Seoul, Korea.
Denise L
DL
Cecil
Authors' Affiliations: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Miami, Miami, Florida; and Division of Oncology/Hematology, Department of Internal Medicine, Korea University, Seoul, Korea.
Gregory E
GE
Holt
Authors' Affiliations: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Miami, Miami, Florida; and Division of Oncology/Hematology, Department of Internal Medicine, Korea University, Seoul, Korea.
Kyong Hwa
KH
Park
Authors' Affiliations: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Miami, Miami, Florida; and Division of Oncology/Hematology, Department of Internal Medicine, Korea University, Seoul, Korea.
Ekram
E
Gad
Authors' Affiliations: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Miami, Miami, Florida; and Division of Oncology/Hematology, Department of Internal Medicine, Korea University, Seoul, Korea.
Lauren
L
Rastetter
Authors' Affiliations: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Miami, Miami, Florida; and Division of Oncology/Hematology, Department of Internal Medicine, Korea University, Seoul, Korea.
Jennifer
J
Childs
Authors' Affiliations: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Miami, Miami, Florida; and Division of Oncology/Hematology, Department of Internal Medicine, Korea University, Seoul, Korea.
Doreen
D
Higgins
Authors' Affiliations: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Miami, Miami, Florida; and Division of Oncology/Hematology, Department of Internal Medicine, Korea University, Seoul, Korea ndisis@uw.edu.
Mary L
ML
Disis
D000818:Animals; D000915:Antibody Affinity; D000951:Antigens, Neoplasm / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology*; D002460:Cell Line; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; C577903:IGFBP2 protein, human; C508609:IL10 protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D016753:Interleukin-10; D007371:Interferon-gamma