Triple-Triple-Negative Breast Cancer Shapes the Systemic Immune Landscape and Alters Neutrophil Functionality

Cancer dysregulates intratumoral adaptive-innate immune cell crosstalk, however, it remains largely unknown how the systemic immune landscape is modified during breast cancer progression and whether prior chemotherapy treatment exerts persistent changes on circulating immune cells. Here, we comprehensively profiled the systemic immune landscape in patients with triple negative breast cancer (TNBC) at distinct disease stages, to understand how cancer progression and treatment history shape the systemic immune landscape. We performed multi-parameter flow cytometry analysis to assess the global systemic immune landscape, including often overlooked granulocytes. We showed that patients with metastatic TNBC (mTNBC) exhibited increased classical monocytes and neutrophils compared to healthy donors (HDs) irrespective of prior therapy. Conversely, circulating T cells, dendritic cell subsets and differentiated B cells were reduced in patients with mTNBC compared to HDs, which could partially be attributed to prior chemotherapy treatment. Phenotypic and functional characterization of the T cell compartment revealed increased IL17 production by vδ1 γδ T cells, were increased. Transcriptional and proteomic analysis, alongside ex vivo functionality assays, revealed increased migratory capacity, increased granule proteins, and elevated ROS production in circulating neutrophils of mTNBC patients. Our data demonstrate that patient neutrophils are not only more abundant, but also display an altered functionality, underscoring the significant impact of TNBC disease stage and treatment history on the systemic immune composition and function.

癌症可失调肿瘤内适应性免疫与先天免疫细胞的相互串扰，但目前学界仍未充分阐明乳腺癌进展过程中全身免疫格局（systemic immune landscape）的改变模式，以及既往化疗是否会对循环免疫细胞产生持久性影响。本研究针对不同疾病分期的三阴性乳腺癌（triple negative breast cancer, TNBC）患者，全面解析了其全身免疫格局，以期明确癌症进展与治疗史如何塑造全身免疫状态。我们采用多参数流式细胞术（multi-parameter flow cytometry）分析，对涵盖常被忽视的粒细胞在内的全身整体免疫状态进行了评估。研究结果显示，相较于健康受试者（healthy donors, HDs），转移性三阴性乳腺癌（metastatic TNBC, mTNBC）患者的经典单核细胞与中性粒细胞比例升高，且该现象与既往治疗史无关。与之相反，转移性三阴性乳腺癌患者的循环T细胞、树突状细胞亚群及分化型B细胞数量均有所减少，该改变在一定程度上可归因于既往化疗。对T细胞区室的表型与功能特征分析显示，Vδ1型γδ T细胞的白细胞介素17（IL-17）产生量显著升高。转录组学与蛋白质组学分析结合离体功能实验结果表明，转移性三阴性乳腺癌患者的循环中性粒细胞具备更强的迁移能力、更高水平的颗粒蛋白表达，且活性氧（reactive oxygen species, ROS）生成量增加。本研究数据证实，患者体内的中性粒细胞不仅数量更为丰富，其功能也发生了改变，这凸显了三阴性乳腺癌的疾病分期与治疗史对全身免疫组成及功能的显著影响。