T-helper I immunity, specific for the breast cancer antigen insulin-like growth factor-I receptor (IGF-IR), is associated with increased adiposity

Abstract

Numerous lines of evidence demonstrate that breast cancer is immunogenic; yet, there are few biologically relevant immune targets under investigation restricting the exploration of vaccines to limited breast cancer subtypes. Insulin-like growth factor-I receptor (IGF-IR) is a promising vaccine candidate since it is overexpressed in most breast cancer subtypes, is part of a dominant cancer growth pathway, and has been validated as a therapeutic target. We questioned whether IGF-IR was immunogenic in cancer patients. IGF-IR-specific IgG antibodies were significantly elevated in early-stage breast cancer patients at the time of diagnosis as compared to volunteer donors (p = 0.04). Predicted T-helper epitopes, derived from the IGF-IR extracellular and transmembrane domains, elicited a significantly higher incidence of Th2 immunity in breast cancer patients as compared to controls (p = 0.01). Moreover, the magnitude of Th2 immunity was greater in breast cancer patients compared to controls (p = 0.02). In contrast, both breast cancer patients and volunteer donors demonstrated a similar incidence of Th1 immunity to IGF-IR domains with the predominant response directed against epitopes in the intracellular domain of the protein. As the incidence of IGF-IR type I immunity was not associated with a breast cancer diagnosis, we questioned whether other factors were contributing to the presence of IGF-IR-specific T-cells in both populations. While age was not associated with Th1 immunity, we observed a significantly greater magnitude of IGF-IR IFN-γ-secreting T-cells in obese subjects as compared to overweight (p < 0.001) or healthy-weight (p = 0.006) subjects, regardless of breast cancer diagnosis. No significant difference was observed for Th2 incidence or magnitude when stratified by age (p = 0.174, p = 0.966, respectively) or body mass index (p = 0.137, p = 0.174, respectively). Our data demonstrate that IGF-IR is a tumor antigen and IGF-IR-specific Th1 immunity may be associated with obesity rather than malignancy.

Designing Vaccines to Prevent Breast Cancer Recurrence or Invasive Disease

“…Three examples of possible preinvasive antigen targets include IGF1R, IGFBP2 and HER2. IGF1R is overexpressed in both preinvasive and invasive breast cancer and has increased autoantibodies in breast cancer patients as compared with normal donors (p < 0.04) [10]. Increased autoantibodies to IGFBP2 have been seen in breast cancer patients over controls (p = 0.0008) and IGFBP2 has been shown to be important in pathogenesis of both preinvasive and invasive breast cancer [11].…”

“…For example, PBMC from breast cancer patients had an increased Th2 response to MHC class II predicted IGF1R epitopes as compared to matched normal controls [10]. Th1 immune response both destroys the current disease and provides immunologic memory to protect against recurrence or progression because of IFN-γ associated inflammatory cytokines which are necessary for enhanced function of antigen presenting cells, epitope spreading, activation of the CD8 + T cells and immunologic memory [15, 16].…”

Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo

“…IgG specific for HIF-1α was assessed by indirect ELISA as previously described with the following modifications; recombinant HIF-1α (500 ng/ml) (Abnova) was used as the coating antigen and the sera was diluted 1:200 in 1% human serum albumin/PBS buffer (12). The ΔOD was calculated as the OD of the protein-coated wells minus the OD of the buffer-coated wells.…”

“…Positive responses were defined by a statistically significant difference (p<0.05) between the mean number of spots from five replicates in the experimental wells and the mean number from no antigen control wells. T-cell lines were generated as previously described from volunteer controls demonstrating significant responses to the selected epitopes (12). Data are reported as the mean number of spots for each experimental antigen minus the mean number of spots detected in no antigen control wells ± SEM or SD (corrected spots per well: CSPW per 2×10 5 PBMC or 4.5×10 5 splenic cells).…”

Elimination of IL-10–Inducing T-Helper Epitopes from an IGFBP-2 Vaccine Ensures Potent Antitumor Activity

“…Peripheral blood mononuclear cells (PBMC) from 20 female breast cancer patients, obtained by a University of Washington institutional review board approved informed consent, were cryopreserved and evaluated by ELISPOT for antigen specific IFN-γ or IL-10 secretion, according to our published methods (17, 18). Data are reported as the mean number of spots for each experimental antigen minus the mean number of spots detected in no antigen control wells (corrected spots per well: CSPW).…”