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

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

Research output: Contribution to journalArticle

19 Scopus citations

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
StatePublished - May 15 2014

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cecil, D. L., Holt, G., Park, K. H., Gad, E., Rastetter, L., Childs, J., Higgins, D., & Disis, M. L. (2014). Elimination of IL-10-inducing T-helper epitopes from an IGFBP-2 vaccine ensures potent antitumor activity. Cancer Research, 74(10), 2710-2718. https://doi.org/10.1158/0008-5472.CAN-13-3286