Douglas Hanahan, Olivier Michielin, Mikael J. Pittet
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引用次数: 0
摘要
肿瘤发生体现了一种异型肿瘤微环境(TME)的形成,这种微环境具有多种功能,其中包括能够逃避 T 细胞介导的免疫反应。值得注意的是,大多数 TME 细胞类型,包括癌细胞、成纤维细胞、髓样细胞、血管内皮细胞和周细胞,都能受刺激部署免疫调节程序。这些程序涉及调节诱导因子(信号输入)和功能效应因子(信号输出),它们通过细胞因子、生长因子、免疫检查点和代谢产物损害 CD8+ 和 CD4+ T 细胞的活性。一些信号针对特定的细胞类型,而另一些信号,如转化生长因子-β(TGFβ)和前列腺素 E2(PGE2),则会产生广泛的多效应;作为输入信号,它们会触发大多数 TME 细胞类型的免疫抑制程序,而作为输出信号,它们会直接抑制 T 细胞,并调节其他细胞以加强免疫抑制。这种功能上的多样性和冗余性为针对具有免疫侵袭性的 TME 的治疗带来了挑战。从根本上说,旨在削弱 T 细胞活性的调控程序以及 TME 细胞之间的旁分泌信号的共性表明,许多正常细胞类型都具有潜在功能,可以被触发以防止不适当的免疫攻击。这种固有的能力显然被整个肿瘤组织器官所利用,使肿瘤得以逃避免疫破坏。
Convergent inducers and effectors of T cell paralysis in the tumour microenvironment
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.
期刊介绍:
Nature Reviews Cancer, a part of the Nature Reviews portfolio of journals, aims to be the premier source of reviews and commentaries for the scientific communities it serves. The correct abbreviation for abstracting and indexing purposes is Nat. Rev. Cancer. The international standard serial numbers (ISSN) for Nature Reviews Cancer are 1474-175X (print) and 1474-1768 (online). Unlike other journals, Nature Reviews Cancer does not have an external editorial board. Instead, all editorial decisions are made by a team of full-time professional editors who are PhD-level scientists. The journal publishes Research Highlights, Comments, Reviews, and Perspectives relevant to cancer researchers, ensuring that the articles reach the widest possible audience due to their broad scope.