title: 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.
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, 850 Republican Street, Seattle, WA 98109, USA. dcecil@uw.edu
authors.forename: Denise L
authors.initials: DL
authors.lastname: Cecil
authors.forename: Kyong Hwa
authors.initials: KH
authors.lastname: Park
authors.forename: Ekram
authors.initials: E
authors.lastname: Gad
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Childs
authors.forename: Doreen M
authors.initials: DM
authors.lastname: Higgins
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Plymate
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology*; D016022:Case-Control Studies; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000494:pharmacology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D008875:Middle Aged; D009765:Obesity / Q000276:immunology; D050177:Overweight / Q000276:immunology*; D017434:Protein Structure, Tertiary; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D007371:Interferon-gamma; D017526:Receptor, IGF Type 1