Elimination of IL-10-inducing T-helper epitopes from an IGFBP-2 vaccine ensures potent antitumor activity

Denise L. Cecil, Gregory E. Holt, Kyong Hwa Park, Ekram Gad, Lauren Rastetter, Jennifer Childs, Doreen Higgins, Mary L. Disis

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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-g 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 T H1/TH2 responses. Epitopespecific 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 naεve 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.

Original languageEnglish
Pages (from-to)2710-2718
Number of pages9
JournalCancer Research
Volume74
Issue number10
DOIs
Publication statusPublished - 2014 May 15

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Insulin-Like Growth Factor Binding Protein 2
Interleukin-10
Epitopes
Vaccines
T-Lymphocytes
Cancer Vaccines
Autoantigens
Neoplasm Antigens
Immunosuppressive Agents
Neoplasms
Growth
Cytokines
Enzyme-Linked Immunospot Assay
T-Lymphocyte Epitopes
Regulatory T-Lymphocytes
Immunity
Immunization
Lymphocytes
Breast Neoplasms
Antigens

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Elimination of IL-10-inducing T-helper epitopes from an IGFBP-2 vaccine ensures potent antitumor activity. / Cecil, Denise L.; Holt, Gregory E.; Park, Kyong Hwa; Gad, Ekram; Rastetter, Lauren; Childs, Jennifer; Higgins, Doreen; Disis, Mary L.

In: Cancer Research, Vol. 74, No. 10, 15.05.2014, p. 2710-2718.

Research output: Contribution to journalArticle

Cecil, DL, Holt, GE, Park, KH, Gad, E, Rastetter, L, Childs, J, Higgins, D & Disis, ML 2014, 'Elimination of IL-10-inducing T-helper epitopes from an IGFBP-2 vaccine ensures potent antitumor activity', Cancer Research, vol. 74, no. 10, pp. 2710-2718. https://doi.org/10.1158/0008-5472.CAN-13-3286
Cecil, Denise L. ; Holt, Gregory E. ; Park, Kyong Hwa ; Gad, Ekram ; Rastetter, Lauren ; Childs, Jennifer ; Higgins, Doreen ; Disis, Mary L. / Elimination of IL-10-inducing T-helper epitopes from an IGFBP-2 vaccine ensures potent antitumor activity. In: Cancer Research. 2014 ; Vol. 74, No. 10. pp. 2710-2718.
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