Analysis of cancer-related immune suppressor mechanisms in mice

今年特别关注肝脏中的先天免疫细胞，并研究了粘膜相关不变T细胞(MAIT)代表人类肝脏中丰富的先天T细胞亚型。MAITs在调节免疫和炎症方面被指定为关键角色，但它们在肝癌中的作用仍然难以捉摸。在这里，我们提出了一种以MAIT为中心的肝细胞癌的分析方法，使用scRNA-seq、流式细胞术和配对患者样本的37-plex联合检测(CODEX)成像。这些分析突出了肝细胞癌中MAITs的异质性和功能障碍，以及它们渗透到肝脏肿瘤的缺陷能力。新的机器学习工具被用来剖析MAIT邻域内的空间细胞相互作用网络。邻近肝脏的共定位以及占据空位的CSF1R+PD-L1+肿瘤相关巨噬细胞与MAITs的相互作用被认为是MAIT功能障碍的关键调节因素。在使用患者样本和在小鼠模型中进行的体外共培养研究中，这种细胞-细胞相互作用的扰动重新激活了MAIT细胞的细胞毒性。这些研究表明，在肝细胞癌患者中，针对MAITs的apd-1/apd-L1疗法。

This year placed a specific focus on innate immune cells in the liver and studied Mucosal-associated invariant T (MAIT) cells represent an abundant innate-like T cell subtype in the human liver. MAITs are assigned crucial roles in regulating immunity and inflammation, yet their role in liver cancer remains elusive. Here, we present a MAIT- centered profiling of hepatocellular carcinoma (HCC) using scRNA-seq, flow cytometry, and 37-plex co-detection by indexing (CODEX) imaging of paired patient samples. These analyses highlight the heterogeneity and dysfunctionality of MAITs in HCC and their defective capacity to infiltrate liver tumors. Novel machine learning tools were used to dissect the spatial cellular interaction network within the MAIT neighborhood. Co- localization in the adjacent liver and interaction between niche-occupying CSF1R+PD-L1+ tumor-associated macrophages and MAITs was identified as key regulatory element of MAIT dysfunction. Perturbation of this cell-cell interaction in ex vivo co-culture studies using patient samples and in murine models reinvigorated MAIT cell cytotoxicity. These studies suggest that aPD-1/aPD-L1 therapies target MAITs in HCC patients.