Department of Medical Oncology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, North Holland, The Netherlands.
Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, 94115, USA.
Breast Cancer Res. 2023 Oct 4;25(1):117. doi: 10.1186/s13058-023-01717-1.
Despite major improvements in treatment of HER2-positive metastatic breast cancer (MBC), only few patients achieve complete remission and remain progression free for a prolonged time. The tumor immune microenvironment plays an important role in the response to treatment in HER2-positive breast cancer and could contain valuable prognostic information. Detailed information on the cancer-immune cell interactions in HER2-positive MBC is however still lacking. By characterizing the tumor immune microenvironment in patients with HER2-positive MBC, we aimed to get a better understanding why overall survival (OS) differs so widely and which alternative treatment approaches may improve outcome.
We included all patients with HER2-positive MBC who were treated with trastuzumab-based palliative therapy in the Netherlands Cancer Institute between 2000 and 2014 and for whom pre-treatment tissue from the primary tumor or from metastases was available. Infiltrating immune cells and their spatial relationships to one another and to tumor cells were characterized by immunohistochemistry and multiplex immunofluorescence. We also evaluated immune signatures and other key pathways using next-generation RNA-sequencing data. With nine years median follow-up from initial diagnosis of MBC, we investigated the association between tumor and immune characteristics and outcome.
A total of 124 patients with 147 samples were included and evaluated. The different technologies showed high correlations between each other. T-cells were less prevalent in metastases compared to primary tumors, whereas B-cells and regulatory T-cells (Tregs) were comparable between primary tumors and metastases. Stromal tumor-infiltrating lymphocytes in general were not associated with OS. The infiltration of B-cells and Tregs in the primary tumor was associated with unfavorable OS. Four signatures classifying the extracellular matrix of primary tumors showed differential survival in the population as a whole.
In a real-world cohort of 124 patients with HER2-positive MBC, B-cells, and Tregs in primary tumors are associated with unfavorable survival. With this paper, we provide a comprehensive insight in the tumor immune microenvironment that could guide further research into development of novel immunomodulatory strategies.
尽管 HER2 阳性转移性乳腺癌（MBC）的治疗取得了重大进展，但只有少数患者能够完全缓解并长时间保持无进展。肿瘤免疫微环境在 HER2 阳性乳腺癌的治疗反应中起着重要作用，并且可能包含有价值的预后信息。然而，关于 HER2 阳性 MBC 中肿瘤-免疫细胞相互作用的详细信息仍然缺乏。通过对 HER2 阳性 MBC 患者的肿瘤免疫微环境进行特征描述，我们旨在更好地了解为什么总体生存率（OS）差异如此之大，以及哪些替代治疗方法可能改善预后。
我们纳入了 2000 年至 2014 年期间在荷兰癌症研究所接受曲妥珠单抗为基础的姑息治疗的所有 HER2 阳性 MBC 患者，并且这些患者在初诊时存在原发肿瘤或转移灶的组织标本。通过免疫组织化学和多重免疫荧光染色来描述浸润免疫细胞及其相互之间以及与肿瘤细胞之间的空间关系。我们还使用下一代 RNA 测序数据评估了免疫特征和其他关键途径。根据 MBC 初诊后的 9 年中位随访时间，我们研究了肿瘤和免疫特征与预后之间的关系。
共纳入了 124 例患者的 147 个样本进行评估。不同技术之间显示出高度相关性。与原发肿瘤相比，转移灶中 T 细胞的比例较低，而 B 细胞和调节性 T 细胞（Tregs）在原发肿瘤和转移灶之间相当。一般来说，基质肿瘤浸润淋巴细胞与 OS 无关。原发肿瘤中 B 细胞和 Tregs 的浸润与不良的 OS 相关。4 个分类原发性肿瘤细胞外基质的特征性标记在整个人群中显示出不同的生存情况。
在 124 例 HER2 阳性 MBC 患者的真实世界队列中，原发肿瘤中的 B 细胞和 Tregs 与不良生存相关。通过本研究，我们全面了解了肿瘤免疫微环境，这可能为开发新的免疫调节策略提供指导。
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