Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients. Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients

Tumor-draining lymph node (TDLN) invasion by metastatic cells in breast cancer correlates with poor prognosis and is associated with local immunosuppression, which can be partly mediated by regulatory T cells (Tregs). Here, we study Tregs from matched tumor-invaded and non-invaded TDLNs, and breast tumors. We observe that Treg frequencies increase with nodal invasion, that Tregs express higher levels of co-inhibitory/stimulatory receptors than effector cells. Also, while Tregs show conserved suppressive function in TDLN and tumor, conventional T cells (Tconvs) in TDLNs proliferate and produce Th1-inflammatory cytokines, but are dysfunctional in the tumor. We describe a common transcriptomic signature shared by Tregs from tumors and nodes, including CD80, which is significantly associated with poor patient survival. TCR RNA-sequencing analysis indicates trafficking between TDLNs and tumors and ongoing Tconv/Treg conversion. Overall, TDLN Tregs are functional and express a distinct pattern of druggable co-receptors, highlighting their potential as targets for cancer immunotherapy.

乳腺癌中，肿瘤引流淋巴结（Tumor-draining Lymph Node, TDLN）被肿瘤转移细胞侵袭与患者不良预后相关，且与局部免疫抑制有关，而该免疫抑制可部分由调节性T细胞（Tregs）介导。本研究针对配对的肿瘤侵袭型与非侵袭型肿瘤引流淋巴结，以及乳腺癌组织中的调节性T细胞展开分析。研究发现，调节性T细胞的占比随淋巴结侵袭程度升高而增加，且其共抑制/共刺激受体的表达水平高于效应细胞。同时，尽管调节性T细胞在肿瘤引流淋巴结与肿瘤组织中均保留了免疫抑制功能，但肿瘤引流淋巴结内的常规T细胞（Conventional T Cells, Tconvs）可增殖并分泌Th1型炎症细胞因子，而在肿瘤组织中其功能却出现失调。本研究还鉴定出肿瘤组织与淋巴结中的调节性T细胞共有的转录组特征，其中包括CD80，该分子与患者不良生存结局显著相关。T细胞受体RNA测序（TCR RNA-sequencing）分析结果显示，肿瘤引流淋巴结与肿瘤组织间存在细胞迁移，且常规T细胞与调节性T细胞间存在持续的转化过程。综上，肿瘤引流淋巴结内的调节性T细胞具备免疫抑制功能，且表达具有独特特征的可靶向共受体谱，这凸显了其作为癌症免疫治疗靶点的潜力。