小柯机器人

比利时VIB癌症生物学中心Gabriele Bergers研究团队发现，癌症免疫疗法将内皮细胞转变为产生TCF1⁺T淋巴细胞微环境的HEV。该研究于2022年11月23日在线发表于国际一流学术期刊《癌细胞》。

研究人员表示，T细胞浸润的缺乏是癌症有效免疫治疗的一个主要障碍。相反，肿瘤相关三级淋巴结样结构（TA-TLLS）的形成，是针对癌症的体液和细胞免疫反应的局部部位，与良好的预后有关，而且最近在免疫检查点阻断（ICB）反应的患者中检测到了这些结构。然而，对这些淋巴细胞聚集体如何发展仍然知之甚少。

通过采用单细胞转录组学、内皮细胞命运图谱和功能性多重免疫分析，研究人员证明了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）信号诱发毛细血管后静脉转分化为炎性高内皮细胞微静脉（HEV）。反过来，肿瘤HEV促进了瘤内淋巴细胞的流入，并为分化为GrzB⁺PD1⁺CD8 T效应细胞的PD1^-和PD1⁺TCF1⁺CD8 T细胞祖细胞培育了淋巴细胞微环境。肿瘤HEV需要持续的CD8和NK细胞来源的信号，这表明肿瘤HEV的维持是由适应性免疫系统通过前馈环路来主动塑造的。

附：英文原文

Title: Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop

Author: Yichao Hua, Gerlanda Vella, Florian Rambow, Elizabeth Allen, Asier Antoranz Martinez, Marie Duhamel, Akira Takeda, Sirpa Jalkanen, Steffie Junius, Ann Smeets, David Nittner, Stefanie Dimmeler, Thomas Hehlgans, Adrian Liston, Francesca Maria Bosisio, Giuseppe Floris, Damya Laoui, Maija Hollmén, Diether Lambrechts, Pascal Merchiers, Jean-Christophe Marine, Susan Schlenner, Gabriele Bergers

Issue&Volume: 2022-11-23

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.

DOI: 10.1016/j.ccell.2022.11.002

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00549-9

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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