Loss of Anti-HER-3 CD4+ T-Helper Type 1 Immunity Occurs in Breast Tumorigenesis and is Negatively Associated with Outcomes

• Published in: Annals of surgical oncology Vol. 24; no. 2; pp. 407 - 417
• Main Authors: Fracol, Megan, Datta, Jashodeep, Lowenfeld, Lea, Xu, Shuwen, Zhang, Paul J., Fisher, Carla S., Czerniecki, Brian J.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2017; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Breast Neoplasms - drug therapy; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Breast Oncology; Carcinogenesis - drug effects; Carcinogenesis - immunology; Carcinogenesis - pathology; Carcinoma, Intraductal, Noninfiltrating - drug therapy; Carcinoma, Intraductal, Noninfiltrating - immunology; Carcinoma, Intraductal, Noninfiltrating - pathology; CD4-Positive T-Lymphocytes - immunology; Female; Follow-Up Studies; Humans; Medicine; Medicine & Public Health; Middle Aged; Neoadjuvant Therapy; Neoplasm, Residual - drug therapy; Neoplasm, Residual - immunology; Neoplasm, Residual - pathology; Oncology; Prognosis; Receptor, ErbB-2 - metabolism; Receptor, ErbB-3 - immunology; Receptors, Estrogen - metabolism; Surgery; Surgical Oncology; Survival Rate; Th1 Cells - immunology; TNBC Patient; Invasive Breast Cancer; HER3 Overexpression; HER3 Expression; Breast Tumorigenesis
• ISSN: 1068-9265; 1534-4681; 1534-4681
• DOI: 10.1245/s10434-016-5584-6

Background We previously demonstrated a progressive loss of the anti-human epidermal growth factor receptor 2 (HER2) CD4+ T-helper type 1 (Th1) response during HER2 pos breast tumorigenesis. This loss is associated with residual disease following neoadjuvant therapy and increased risk of recurrence. In this study, we assessed the fate of anti-HER3 Th1 immunity during breast tumorigenesis. Methods Peripheral blood from 131 subjects, including healthy donors (HDs), patients with benign breast disease (BD), ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC), was collected. Interferon (IFN)-γ pos immune responses to four HER3-derived major histocompatibility complex (MHC) class II promiscuous peptides were tested via enzyme-linked immunosorbent (ELISPOT) assays, and three immune response parameters were compared: anti-HER3 (i) responsivity, or proportion of subjects responding to at least one peptide; (ii) repertoire, or number of responding peptides; and (iii) cumulative response, or summed peptide response. Results A significant decline in anti-HER3 Th1 response was observed going from HDs to IBC patients; patients with triple-negative breast cancer (TNBC) demonstrated the lowest responses. HDs had significantly higher Th1 responses versus estrogen receptor (ER) pos IBC and TNBC patients across all three immune parameters; HER2 pos IBC patients displayed responses similar to HDs and BDs. Patients with recurrent breast cancer and residual disease following neoadjuvant therapy demonstrated significantly lower anti-HER3 Th1 immunity compared with patients without recurrence or with a pathologic complete response to neoadjuvant therapy. Conclusions Anti-HER3 CD4+ Th1 responses decline during breast tumorigenesis, particularly in TNBC. Attempts to immunologically restore depressed responses in vulnerable subgroups may help mitigate recurrence.