The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma.
The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma.
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DOI：
10.1136/gutjnl-2021-325288
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发表时间：
2022-06
期刊：
影响因子：
24.5
通讯作者：
Korangy F
中科院分区：
文献类型：
--
作者：
Heinrich B;Gertz EM;Schäffer AA;Craig A;Ruf B;Subramanyam V;McVey JC;Diggs LP;Heinrich S;Rosato U;Ma C;Yan C;Hu Y;Zhao Y;Shen TW;Kapoor V;Telford W;Kleiner DE;Stovroff MK;Dhani HS;Kang J;Fishbein T;Wang XW;Ruppin E;Kroemer A;Greten TF;Korangy F
肝细胞癌（HCC）是一种典型的炎症相关癌症。组织常驻先天淋巴样细胞（ILCs）被认为控制肿瘤监测。在这里，我们研究了局部细胞因子环境如何控制肝癌中的ILCs。我们对来自48例HCC患者的非肿瘤肝脏、边缘和肿瘤核心的富集ILCs进行了大量RNA测序，流式细胞术和单细胞RNA测序。在单细胞水平（AbSeq）同时测量蛋白质和RNA表达，确定ILC亚群的精确特征。利用体外培养的ILCs来验证计算机分析的结果。来自大型HCC队列的rna测序数据分析允许基于转录组特征的分层和生存分析。肿瘤、非肿瘤和切缘的RNA测序发现肿瘤依赖梯度不仅与生存差相关，而且还控制ILC的可塑性。来自HCC肝脏的ILCs的单细胞RNA测序和流式细胞术鉴定了非肿瘤组织中的nk样细胞，当它们转变为肿瘤ILC1和nk样ilc3细胞时，失去了它们的细胞毒性特征。肿瘤ILC的组成受细胞因子梯度的调节，细胞因子梯度引导ILC的可塑性向激活的肿瘤ILC2s方向发展。这是肝脏特异性的，在PBMC的ilc中未见。ILC2/ILC1比值高的患者在肿瘤中表达IL-33，促进了ILC2的生成，与更好的生存率相关。我们的研究结果表明，肿瘤细胞因子环境控制着ILC的组成和HCC的预后。细胞因子的特异性变化通过诱导肿瘤细胞的可塑性改变ILC的组成，从而改变ILC的功能。
Hepatocellular carcinoma (HCC) represents a typical inflammation-associated cancer. Tissue resident innate lymphoid cells (ILCs) have been suggested to control tumor surveillance. Here we studied how the local cytokine milieu controls ILCs in HCC. We performed bulk RNA sequencing of HCC tissue as well as flow cytometry and single-cell RNA sequencing of enriched ILCs from non-tumor liver, margin and tumor core derived from 48 HCC patients. Simultaneous measurement of protein and RNA expression at the single-cell level (AbSeq) identified precise signatures of ILC subgroups. In-vitro culturing of ILCs was used to validate findings from in-silico analysis. Analysis of RNA-sequencing data from large HCC cohorts allowed stratification and survival analysis based on transcriptomic signatures. RNA sequencing of tumor, non-tumor and margin identified tumor-dependent gradients of which were not only associated with poor survival but also control ILC plasticity. Single-cell RNA sequencing and flow cytometry of ILCs from HCC livers identified NK-like cells in the non-tumor tissue, losing their cytotoxic profile as they transitioned into tumor ILC1 and NK-like-ILC3 cells. Tumor ILC composition was mediated by cytokine gradients that directed ILC plasticity towards activated tumor ILC2s. This was liver-specific and not seen in ILCs from PBMC. Patients with high ILC2/ILC1 ratio expressed IL-33 in the tumor that promoted ILC2 generation which was associated with better survival. Our results suggest that the tumor cytokine milieu controls ILC composition and HCC outcome. Specific changes of cytokines modify ILC composition in the tumor by inducing plasticity and alter ILC function.
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影响因子：
32.4
作者：
Colonna M
通讯作者：
Colonna M
IL4诱导与抑制神经炎症的体外和体内抑制有关的产生IL6的M2巨噬细胞。
影响因子：
9.3
作者：
Casella G;Garzetti L;Gatta AT;Finardi A;Maiorino C;Ruffini F;Martino G;Muzio L;Furlan R
通讯作者：
Furlan R
影响因子：
30.5
作者：
Bernink, Jochem H.;Peters, Charlotte P.;Spits, Hergen
通讯作者：
Spits, Hergen
影响因子：
4.6
作者：
Foerster F;Hess M;Gerhold-Ay A;Marquardt JU;Becker D;Galle PR;Schuppan D;Binder H;Bockamp E
通讯作者：
Bockamp E
影响因子：
32.4
作者：
Chen L;Youssef Y;Robinson C;Ernst GF;Carson MY;Young KA;Scoville SD;Zhang X;Harris R;Sekhri P;Mansour AG;Chan WK;Nalin AP;Mao HC;Hughes T;Mace EM;Pan Y;Rustagi N;Chatterjee SS;Gunaratne PH;Behbehani GK;Mundy-Bosse BL;Caligiuri MA;Freud AG
通讯作者：
Freud AG