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.
摘要
肿瘤微环境中T细胞活性的严格调控对于生成保护性的抗肿瘤免疫至关重要。然而，形成促进肿瘤浸润T细胞的关键成纤维支持微环境的细胞的识别、分化和功能仍然不明确。在本研究中，我们发现CCL19表达的成纤维网状细胞（FRCs）在人类非小细胞肺癌中生成互联的T细胞微环境（TEs），包括三级淋巴结构和T细胞轨迹。对FRC-T细胞相互作用组的分析表明，分子网络调控CCL19表达的成纤维细胞的微环境特异性分化以及T细胞激活通路。小鼠单细胞转录组学和细胞命运追踪分析证实，TEs中的FRCs源自血管壁和外膜前体细胞。消除肿瘤内FRC前体细胞会减少抗肿瘤T细胞的活性，导致在冠状病毒载体基础免疫治疗中的肿瘤控制减弱。总之，肿瘤微环境中的特化FRC微环境调控抗肿瘤T细胞免疫的质量和程度。
原文链接
Onder L, Papadopoulou C, Lütge A, Cheng HW, Lütge M, Perez-Shibayama C, Gil-Cruz C, De Martin A, Kurz L, Cadosch N, Pikor NB, Rodriguez R, Born D, Jochum W, Leskow P, Dutly A, Robinson MD, Ludewig B. Fibroblastic reticular cells generate protective intratumoral T cell environments in lung cancer. Cell. 2024 Nov 19:S0092-8674(24)01259-5. doi: 10.1016/j.cell.2024.10.042. Epub ahead of print. PMID: 39566495.
