瑞士圣加仑医院免疫生物学研究所Burkhard Ludewig和Lucas Onder合作取得重要工作进展。他们研究提出，肺癌中成纤维网状细胞产生保护性肿瘤内T细胞环境。相关研究成果2024年11月19日在线发表于《细胞》杂志上。
据介绍，严格控制肿瘤微环境中的T细胞活性，对于产生保护性抗肿瘤免疫至关重要。然而，产生促进肿瘤浸润T细胞的关键成纤维细胞生态位的，身份、分化和功能仍然难以捉摸。
研究人员发现表达CCL19的成纤维网状细胞（FRC），在人类非小细胞肺癌中产生相互连接的T细胞环境（TE），包括三级淋巴结构和T细胞轨道。对TE中FRC-T细胞相互作用组的分析表明，分子网络调节表达CCL19的成纤维细胞的，生态位特异性分化和T细胞活化途径。
小鼠单细胞转录组学和细胞命运图谱分析证实，TE中的FRC起源于壁和外膜祖细胞。肿瘤内FRC前体的消融降低了抗肿瘤T细胞活性，导致基于冠状病毒载体的免疫治疗期间肿瘤控制减少。
总之，肿瘤微环境中特化的FRC生态位，控制着抗肿瘤T细胞免疫的质量和程度。
附：英文原文
Title: Fibroblastic reticular cells generate protective intratumoral T cell environments in lung cancer
Author: Lucas Onder, Chrysa Papadopoulou, Almut Lütge, Hung-Wei Cheng, Mechthild Lütge, Christian Perez-Shibayama, Cristina Gil-Cruz, Angelina De Martin, Lisa Kurz, Nadine Cadosch, Natalia B. Pikor, Regulo Rodriguez, Diana Born, Wolfram Jochum, Pawel Leskow, Andre Dutly, Mark D. Robinson, Burkhard Ludewig
Issue&Volume: 2024-11-19
Abstract: Stringent control of T cell activity in the tumor microenvironment is essential for the generation of protective antitumor immunity. However, the identity, differentiation, and functions of the cells that create critical fibroblastic niches promoting tumor-infiltrating T cells remain elusive. Here, we show that CCL19-expressing fibroblastic reticular cells (FRCs) generate interconnected T cell environments (TEs) in human non-small cell lung cancer, including tertiary lymphoid structures and T cell tracks. Analysis of the FRC-T cell interactome in TEs indicated molecular networks regulating niche-specific differentiation of CCL19-expressing fibroblasts and T cell activation pathways. Single-cell transcriptomics and cell fate-mapping analyses in mice confirmed that FRCs in TEs originate from mural and adventitial progenitors. Ablation of intratumoral FRC precursors decreased antitumor T cell activity, resulting in reduced tumor control during coronavirus vector-based immunotherapy. In summary, specialized FRC niches in the tumor microenvironment govern the quality and extent of antitumor T cell immunity.
DOI: 10.1016/j.cell.2024.10.042
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01259-5