Insulin-like Growth Factor–Binding Protein-2 Is a Target for the Immunomodulation of Breast Cancer

Abstract

Breast cancer is immunogenic and well suited to treatment via immunomodulation. The disease is often treated to remission and time to relapse is generally measured in years in many cases. Immune-based therapeutics, such as cancer vaccines, may be able to affect the clinical progression of micrometastatic disease. Immune targets must be identified that have the potential to inhibit tumor growth. Insulin-like growth factor-binding protein-2 (IGFBP-2) has direct effects on breast cancer proliferation via stimulation of critical signaling pathways. We questioned whether IGFBP-2 was an immune target in breast cancer. IGFBP-2-specific IgG antibody immunity was preferentially detected in breast cancer patients compared with controls (P = 0.0008). To evaluate for the presence of T-cell immunity, we identified potential pan-HLA-DR binding epitopes derived from IGFBP-2 and tested the peptides for immunogenicity. The majority of epitopes elicited peptide-specific T cells in both patients and controls and had high sequence homology to bacterial pathogens. IGFBP-2 peptide-specific T cells could respond to naturally processed and presented IGFBP-2 protein, indicating that these peptides were native epitopes of IGFBP-2. Finally, both immunization with IGFBP-2 peptides as well as adoptive transfer of IGFBP-2-competent T cells mediated an antitumor effect in a transgenic mouse model of breast cancer. This is the first report of IGFBP-2 as a human tumor antigen that may be a functional therapeutic target in breast cancer. [Cancer Res 2008;68(20):8400-9]

Plasma Insulin-Like Growth Factor-Binding Protein-2 Levels as Diagnostic and Prognostic Biomarker of Colorectal Cancer

“…This viewpoint is supported by the in vitro studies showing that the administration of OGX-225, an antisense oligonucleotide of IGFBP-2, in breast cancer cells lead to decreased IGFBP-2 expression and attenuated the aggressive phenotype (30). In a transgenic mouse model, immunization with IGFBP-2 peptides and transfer of IGFBP-2-competent T cells also showed antitumor effect of breast cancer (36). The result from the present study provided epidemiological evidence that IGFBP-2 might be a potential therapeutic target for CRC therapy.…”

Novel anti IGFBP2 single chain variable fragment inhibits glioma cell migration and invasion

“…IGFBP2 has been proposed as a therapeutic target for GBM in several studies [18,19,21,25,26] Until now, there has been no demonstration of inhibition of secretory IGFBP2 in controlling GBM cell migration and invasion. Hence, there is an urgent need to develop inhibitors of IGFBP2, which may be useful in the management of GBM.…”

Th1 epitope selection for clinically effective cancer vaccines

“…8 Prior investigations have demonstrated that T cells specific for IGFBP-2 peptides are cross reactive against highly homologous pathogenderived proteins as well as IGFBP-2. 9 Furthermore, the incidence and magnitude of Th2-based immune responses against IGFBP-2 have been found to exceed that of Th1-immunity in individuals screened for Type I and Type II responses. Ongoing studies are evaluating the relationship between the IGFBP-2 Th2-inducing peptides with homologous bacterial proteins that are commonly expressed by flora potentially present in the gastrointestinal tract.…”