title: A different immunologic profile characterizes patients with HER-2-overexpressing and HER-2-negative locally advanced breast cancer: implications for immune-based therapies.
abstract: BACKGROUND
  The clinical efficacy of trastuzumab and taxanes is at least partly related to their ability to mediate or promote antitumor immune responses. On these grounds, a careful analysis of basal immune profile may be capital to dissect the heterogeneity of clinical responses to these drugs in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy.
  
  
  METHODS
  Blood samples were collected from 61 locally advanced breast cancers (36 HER2- and 25 HER2+) at diagnosis and from 23 healthy women. Immunophenotypic profiling of circulating and intratumor immune cells, including regulatory T (Treg) cells, was assessed by flow cytometry and immunohistochemistry, respectively. Serum levels of 10 different cytokines were assessed by multiplex immunoassays. CD8+ T cell responses to multiple tumor-associated antigens (TAA) were evaluated by IFN-γ-enzyme-linked immunosorbent spot (ELISPOT). The Student's t test for two tailed distributions and the Wilcoxon two-sample test were used for the statistical analysis of the data.
  
  
  RESULTS
  The proportion of circulating immune effectors was similar in HER2+ patients and healthy donors, whereas higher percentages of natural killer and Treg cells and a lower CD4+/CD8+ T cell ratio (with a prevalence of naïve and central memory CD8+ T cells) were observed in HER2- cases. Higher numbers of circulating CD8+ T cells specific for several HLA-A*0201-restricted TAA-derived peptides were observed in HER2+ cases, together with a higher prevalence of intratumor CD8+ T cells. Serum cytokine profile of HER2+ patients was similar to that of controls, whereas HER2- cases showed significantly lower cytokine amounts compared to healthy women (IL-2, IL-8, IL-6) and HER2+ cases (IL-2, IL-1β, IL-8, IL-6, IL-10).
  
  
  CONCLUSIONS
  Compared to HER2- cases, patients with HER2-overexpressing locally advanced breast cancer show a more limited tumor-related immune suppression. This may account for the clinical benefit achieved in this subset of patients with the use of drugs acting through, but also promoting, immune-mediated effects.
authors: Cancer Bio-Immunotherapy Unit, Centro di Riferimento Oncologico, IRCCS - National Cancer Institute, via Franco Gallini 2, Aviano (PN), 33081, Italy.
authors: Elena
authors: E
authors: Muraro
authors: Debora
authors: D
authors: Martorelli
authors: Elisa
authors: E
authors: Turchet
authors: Gianmaria
authors: G
authors: Miolo
authors: Simona
authors: S
authors: Scalone
authors: Elisa
authors: E
authors: Comaro
authors: Renato
authors: R
authors: Talamini
authors: Katy
authors: K
authors: Mastorci
authors: Davide
authors: D
authors: Lombardi
authors: Tiziana
authors: T
authors: Perin
authors: Antonino
authors: A
authors: Carbone
authors: Andrea
authors: A
authors: Veronesi
authors: Diana
authors: D
authors: Crivellari
authors: Riccardo
authors: R
authors: Dolcetti
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases