Cancer Bio-Immunotherapy Unit, Centro di Riferimento Oncologico, IRCCS - National Cancer Institute, via Franco Gallini 2, Aviano (PN), 33081, Italy.
Breast Cancer Res. 2011;13(6):R117. doi: 10.1186/bcr3060.
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.
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.
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).
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.
曲妥珠单抗和紫杉类药物的临床疗效至少部分与其介导或促进抗肿瘤免疫反应的能力有关。基于这些原因，仔细分析基础免疫特征对于剖析接受新辅助化疗的局部晚期乳腺癌患者对这些药物的临床反应异质性可能至关重要。
在诊断时采集了 61 例局部晚期乳腺癌（36 例 HER2-和 25 例 HER2+）和 23 例健康女性的血液样本。通过流式细胞术和免疫组织化学分别评估循环和肿瘤内免疫细胞的免疫表型谱，包括调节性 T（Treg）细胞。通过多重免疫测定法评估 10 种不同细胞因子的血清水平。通过 IFN-γ酶联免疫斑点（ELISPOT）评估 CD8+T 细胞对多种肿瘤相关抗原（TAA）的反应。使用双尾分布的学生 t 检验和 Wilcoxon 两样本检验对数据进行统计分析。
HER2+患者和健康供体的循环免疫效应物比例相似，而 HER2-病例中自然杀伤细胞和 Treg 细胞的比例较高，CD4+/CD8+T 细胞比值较低（幼稚和中央记忆 CD8+T 细胞占优势）。在 HER2+病例中观察到针对几种 HLA-A*0201 限制性 TAA 衍生肽的循环 CD8+T 细胞数量增加，并且肿瘤内 CD8+T 细胞的比例也更高。HER2+患者的血清细胞因子谱与对照组相似，而 HER2-病例与健康女性（IL-2、IL-8、IL-6）和 HER2+病例（IL-2、IL-1β、IL-8、IL-6、IL-10）相比，细胞因子量显著降低。
与 HER2-病例相比，HER2 过表达的局部晚期乳腺癌患者表现出更有限的肿瘤相关免疫抑制。这可能解释了在这部分患者中使用通过但也促进免疫介导作用的药物所获得的临床益处。
