Abstract
IntroductionThe 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.MethodsBlood 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-Ī³-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.ResultsThe 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 naĆÆve 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-1Ī², IL-8, IL-6, IL-10).ConclusionsCompared 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.
Highlights
The clinical efficacy of trastuzumab and taxanes is at least partly related to their ability to mediate or promote antitumor immune responses
The results presented demonstrate that patients with human epidermal growth factor receptor-2 (HER2)+ and HER2- breast cancer have a different basal immunologic profile
HER2+ and HER2- patients exhibit a different distribution of circulating and intratumor immune cells The distribution of different circulating immune populations was investigated at diagnosis by multiparametric flow cytometry comparing 17 women with HER2-overexpressing cancers, 20 women with HER2- tumors, and 17 healthy women, who were considered as controls
Summary
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. Breast cancers that overexpress human epidermal growth factor receptor-2 (HER2) are characterized by a poor prognosis [4,5], higher rates of complete responses are currently achieved in HER2+ patients by standard chemotherapy, mainly in association with trastuzumab [6,7], in comparison with HER2- patients. Taxanes induce macrophage-mediated tumor death, stimulate the production of pro-inflammatory cytokines (TNF-a, IL-12, and IL-1), and increase lymphokine activated killer (LAK) cell and natural killer (NK) cell antitumor activity [10,11]
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