PDF(Pubmed)
Abstract：
The lack of T cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLLSs), which are the local site of humoral and cellular immune responses against cancers, is associated with good prognosis, and they have recently been detected in immune checkpoint blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs) via lymphotoxin/lymphotoxin beta receptor (LT/LTβR) signaling. In turn, tumor HEVs boost intratumoral lymphocyte influx and foster permissive lymphocyte niches for PD1- and PD1+TCF1+ CD8 T cell progenitors that differentiate into GrzB+PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.
摘要：
缺乏T细胞浸润是癌症有效免疫疗法的主要障碍。相反，肿瘤相关三级淋巴样结构（TA-TLLS）的形成，它们是针对癌症的体液和细胞免疫反应的局部位点，与良好的预后有关，最近在免疫检查点阻断（ICB）反应患者中发现了它们。然而,这些淋巴聚集体是如何发展的仍然知之甚少。通过使用单细胞转录组学，内皮命运图，和功能多重免疫分析，我们证明,抗血管生成免疫调节疗法通过淋巴毒素/淋巴毒素β受体(LT/LTβR)信号传导,诱导毛细血管后小静脉转分化为发炎的高内皮小静脉(HEV).反过来,肿瘤HEV促进肿瘤内淋巴细胞流入，并促进PD1-和PD1+TCF1+CD8T细胞祖细胞分化为GrzB+PD1+CD8T效应细胞的许可淋巴细胞生态位。肿瘤HEV需要连续的CD8和NK细胞衍生的信号，这表明肿瘤HEV的维持是由适应性免疫系统通过前馈回路积极塑造的。
