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Open Access Research article

A different immunologic profile characterizes patients with HER-2-overexpressing and HER-2-negative locally advanced breast cancer: implications for immune-based therapies

Elena Muraro1, Debora Martorelli1, Elisa Turchet2, Gianmaria Miolo2, Simona Scalone2, Elisa Comaro1, Renato Talamini3, Katy Mastorci1, Davide Lombardi2, Tiziana Perin4, Antonino Carbone4, Andrea Veronesi2, Diana Crivellari2 and Riccardo Dolcetti1*

Author Affiliations

1 Cancer Bio-Immunotherapy Unit, Centro di Riferimento Oncologico, IRCCS - National Cancer Institute, via Franco Gallini 2, Aviano (PN), 33081, Italy

2 Division of Medical Oncology C, Centro di Riferimento Oncologico, IRCCS - National Cancer Institute, via Franco Gallini 2, Aviano (PN), 33081, Italy

3 Epidemiology and Biostatistics Unit, Centro di Riferimento Oncologico, IRCCS - National Cancer Institute, via Franco Gallini 2, Aviano (PN), 33081, Italy

4 Division of Pathology, Centro di Riferimento Oncologico, IRCCS - National Cancer Institute, via Franco Gallini 2, Aviano (PN), 33081, Italy

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Breast Cancer Research 2011, 13:R117  doi:10.1186/bcr3060

Published: 23 November 2011

Abstract

Introduction

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.

Keywords:
Breast cancer; neoadjuvant therapy; HER2; trastuzumab; antitumor immune responses; tumor-associated antigens