文章：

肿瘤微环境中T细胞麻痹的趋同诱导剂和效应剂

Convergent inducers and effectors of T cell paralysis in the tumour microenvironment

原文发布日期：2024-10-24

DOI: 10.1038/s41568-024-00761-z

类型: Review Article

开放获取: 否

英文摘要：

Tumorigenesis embodies the formation of a heterotypic tumour microenvironment (TME) that, among its many functions, enables the evasion of T cell-mediated immune responses. Remarkably, most TME cell types, including cancer cells, fibroblasts, myeloid cells, vascular endothelial cells and pericytes, can be stimulated to deploy immunoregulatory programmes. These programmes involve regulatory inducers (signals-in) and functional effectors (signals-out) that impair CD8+ and CD4+ T cell activity through cytokines, growth factors, immune checkpoints and metabolites. Some signals target specific cell types, whereas others, such as transforming growth factor-β (TGFβ) and prostaglandin E2 (PGE2), exert broad, pleiotropic effects; as signals-in, they trigger immunosuppressive programmes in most TME cell types, and as signals-out, they directly inhibit T cells and also modulate other cells to reinforce immunosuppression. This functional diversity and redundancy pose a challenge for therapeutic targeting of the immune-evasive TME. Fundamentally, the commonality of regulatory programmes aimed at abrogating T cell activity, along with paracrine signalling between cells of the TME, suggests that many normal cell types are hard-wired with latent functions that can be triggered to prevent inappropriate immune attack. This intrinsic capability is evidently co-opted throughout the TME, enabling tumours to evade immune destruction.

摘要翻译： 

肿瘤发生体现了异质性肿瘤微环境的形成，该环境具有多种功能，其中包括使肿瘤能够逃逸T细胞介导的免疫应答。值得注意的是，肿瘤微环境中的大多数细胞类型——包括癌细胞、成纤维细胞、髓系细胞、血管内皮细胞和周细胞——均可被刺激启动免疫调节程序。这些程序涉及调节诱导信号（信号输入）和功能效应信号（信号输出），通过细胞因子、生长因子、免疫检查点和代谢物损害CD8+和CD4+T细胞的活性。部分信号靶向特定细胞类型，而其他信号（如转化生长因子-β和前列腺素E2）则产生广泛的多效作用：作为输入信号时，它们会触发大多数肿瘤微环境细胞类型的免疫抑制程序；作为输出信号时，它们不仅直接抑制T细胞，还能调控其他细胞以增强免疫抑制。这种功能多样性与冗余性为免疫逃逸性肿瘤微环境的治疗靶向带来了挑战。从根本上说，旨在消除T细胞活性的调节程序的普遍性，以及肿瘤微环境细胞间的旁分泌信号传导，表明许多正常细胞类型天生具备潜藏功能，这些功能可被触发以防止不适当的免疫攻击。这种内在能力显然被整个肿瘤微环境所利用，使肿瘤得以逃避免疫摧毁。

原文链接：

Convergent inducers and effectors of T cell paralysis in the tumour microenvironment