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

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.