在HCC浸润边缘肿瘤相关巨噬细胞引发MAIT细胞功能障碍。
Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin.
发表日期：2023 Aug 17
作者：
Benjamin Ruf, Matthias Bruhns, Sepideh Babaei, Noemi Kedei, Lichun Ma, Mahler Revsine, Mohamed-Reda Benmebarek, Chi Ma, Bernd Heinrich, Varun Subramanyam, Jonathan Qi, Simon Wabitsch, Benjamin L Green, Kylynda C Bauer, Yuta Myojin, Layla T Greten, Justin D McCallen, Patrick Huang, Rajiv Trehan, Xin Wang, Amran Nur, Dana Qiang Murphy Soika, Marie Pouzolles, Christine N Evans, Raj Chari, David E Kleiner, William Telford, Kimia Dadkhah, Allison Ruchinskas, Merrill K Stovroff, Jiman Kang, Kesha Oza, Mathuros Ruchirawat, Alexander Kroemer, Xin Wei Wang, Manfred Claassen, Firouzeh Korangy, Tim F Greten
来源：
CELL
摘要：
黏膜相关性不变T细胞（MAIT细胞）是人类肝脏中丰富的类固有T细胞亚型。MAIT细胞在调节免疫和炎症方面起着至关重要的作用，然而其在肝癌中的作用尚不清楚。在这里，我们利用单细胞RNA测序（scRNA-seq）、流式细胞术和索引共检测（CODEX）成像技术，对肝细胞癌（HCC）进行了以MAIT细胞为中心的分析，对配对患者样本进行研究。这些分析突出了HCC中MAIT细胞的异质性和功能障碍，以及它们浸润肝肿瘤的缺陷能力。利用机器学习工具分解了MAIT细胞邻域内的空间细胞相互作用网络。在相邻的肝脏中存在CSF1R+PD-L1+肿瘤相关巨噬细胞（TAMs）和MAIT细胞之间的共定位和相互作用被识别为MAIT细胞功能障碍的关键调节元素。利用患者样本和小鼠模型在体外共培养研究中扰乱这种细胞间相互作用可以重新激活MAIT细胞的细胞毒性。这些研究表明，aPD-1/aPD-L1疗法可以靶向治疗HCC患者的MAIT细胞。由Elsevier公司出版。
Mucosal-associated invariant T (MAIT) cells represent an abundant innate-like T cell subtype in the human liver. MAIT cells are assigned crucial roles in regulating immunity and inflammation, yet their role in liver cancer remains elusive. Here, we present a MAIT cell-centered profiling of hepatocellular carcinoma (HCC) using scRNA-seq, flow cytometry, and co-detection by indexing (CODEX) imaging of paired patient samples. These analyses highlight the heterogeneity and dysfunctionality of MAIT cells in HCC and their defective capacity to infiltrate liver tumors. Machine-learning tools were used to dissect the spatial cellular interaction network within the MAIT cell neighborhood. Co-localization in the adjacent liver and interaction between niche-occupying CSF1R+PD-L1+ tumor-associated macrophages (TAMs) and MAIT cells was identified as a key regulatory element of MAIT cell dysfunction. Perturbation of this cell-cell interaction in ex vivo co-culture studies using patient samples and murine models reinvigorated MAIT cell cytotoxicity. These studies suggest that aPD-1/aPD-L1 therapies target MAIT cells in HCC patients.Published by Elsevier Inc.