Loss of Anti-HER-3 CD4+ T-Helper Type 1 Immunity Occurs in Breast Tumorigenesis and is Negatively Associated with Outcomes.
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 HER2posbreast 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)-γposimmune 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)posIBC and TNBC patients across all three immune parameters; HER2posIBC 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.
Harrison Department of Surgical Research, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Megan
M
Fracol
Harrison Department of Surgical Research, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Jashodeep
J
Datta
Harrison Department of Surgical Research, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Lea
L
Lowenfeld
Harrison Department of Surgical Research, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Shuwen
S
Xu
Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Paul J
PJ
Zhang
Harrison Department of Surgical Research, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.|Rena Rowen Breast Center, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Carla S
CS
Fisher
Harrison Department of Surgical Research, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. brian.czerniecki@moffitt.org.|Rena Rowen Breast Center, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. brian.czerniecki@moffitt.org.|Department of Breast Oncology, Moffitt Cancer Center, Tampa, FL, USA. brian.czerniecki@moffitt.org.
Brian J
BJ
Czerniecki
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D063646:Carcinogenesis / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D018365:Neoplasm, Residual / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000276:immunology*; D011960:Receptors, Estrogen / Q000378:metabolism; D015996:Survival Rate; D018417:Th1 Cells / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011960:Receptors, Estrogen; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human