CD4(+) helper T cells endow cDC1 with cancer-impeding functions in the human tumor micro-environment.
CD4(+) helper T cells endow cDC1 with cancer-impeding functions in the human tumor micro-environment.
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DOI：
10.1038/s41467-022-35615-5
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发表时间：
2023-01-13
影响因子：
16.6
通讯作者：
Xiao, Yanling
中科院分区：
文献类型：
--
作者：
Lei, Xin;Khatri, Indu;de Wit, Tom;de Rink, Iris;Nieuwland, Marja;Kerkhoven, Ron;van Eenennaam, Hans;Sun, Chong;Garg, Abhishek D.;Borst, Jannie;Xiao, Yanling
尽管它们在肿瘤微环境（TME）中的丰度较低，但经典的1型树突状细胞（cDC 1）在抗癌免疫中起着关键作用，并且它们的丰度与患者生存率呈正相关。然而，它们与CD 4 + T细胞的相互作用，以潜在地使细胞毒性T淋巴细胞（CTL）反应尚未阐明。在这里，我们表明，与活化的CD 4 + T细胞接触，使人离体cDC 1，但没有其他类型的DC，诱导细胞相关的肿瘤抗原的CTL反应。单细胞转录组学显示，CD 4 + T细胞帮助独特地优化了cDC 1在支持抗原交叉呈递和T细胞引发的许多功能中，而这些变化不适用于其他DC类型。我们通过其转录组学特征与最近定义的肿瘤浸润性DC状态的重叠，在多种人类癌症类型的TME中稳健地识别出“帮助”的cDC 1，所述肿瘤浸润性DC状态被证明是积极预后的。正如从CD 4 + T细胞辅助的功能效应预测的那样，“辅助”cDC 1的转录组学特征与CTL和Thelper（h）−1细胞的肿瘤浸润、总生存期和对PD-1靶向免疫治疗的反应相关。这些发现揭示了CD 4 + T细胞帮助在TME中实现cDC 1功能的关键作用，并可能建立帮助cDC 1转录组签名作为癌症的诊断标志物。经典1型树突状细胞（cDC 1）的存在对癌症的预后有积极影响，但它们与肿瘤微环境中发现的各种T细胞类型的复杂网络尚未得到充分认识。在这里，作者表明，cDC 1与CD 4+辅助T细胞的相遇改变了它们的基因表达特征，这些“帮助”树突状细胞使抗肿瘤细胞毒性T细胞的功能成为可能。
Despite their low abundance in the tumor microenvironment (TME), classical type 1 dendritic cells (cDC1) play a pivotal role in anti-cancer immunity, and their abundance positively correlates with patient survival. However, their interaction with CD4+ T-cells to potentially enable the cytotoxic T lymphocyte (CTL) response has not been elucidated. Here we show that contact with activated CD4+ T-cells enables human ex vivo cDC1, but no other DC types, to induce a CTL response to cell-associated tumor antigens. Single cell transcriptomics reveals that CD4+ T-cell help uniquely optimizes cDC1 in many functions that support antigen cross-presentation and T-cell priming, while these changes don’t apply to other DC types. We robustly identify “helped” cDC1 in the TME of a multitude of human cancer types by the overlap in their transcriptomic signature with that of recently defined, tumor-infiltrating DC states that prove to be positively prognostic. As predicted from the functional effects of CD4+ T-cell help, the transcriptomic signature of “helped” cDC1 correlates with tumor infiltration by CTLs and Thelper(h)−1 cells, overall survival and response to PD-1-targeting immunotherapy. These findings reveal a critical role for CD4+ T-cell help in enabling cDC1 function in the TME and may establish the helped cDC1 transcriptomic signature as diagnostic marker in cancer. The presence of classical type 1 dendritic cells (cDC1) positively influences prognosis in cancer, but their intricate networking with the various T cell types found in the tumour microenvironment is not fully appreciated. Here the authors show that cDC1 encounter with CD4+ helper T-cells transforms their gene expression signature, and these “helped” dendritic cells enable the function of anti-tumour cytotoxic T-cells.
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