Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Graduate Program in Microbiology and Immunology (PMI), University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Immunology. 2019 Jul;157(3):232-247. doi: 10.1111/imm.13067. Epub 2019 Jun 3.
Regulatory T (Treg) cells play a crucial role in maintaining self-tolerance and resolution of immune responses by employing multifaceted immunoregulatory mechanisms. However, Treg cells readily infiltrate into the tumor microenvironment (TME) and dampen anti-tumor immune responses, thereby becoming a barrier to effective cancer immunotherapy. There has been a substantial expansion in the development of novel immunotherapies targeting various inhibitory receptors (IRs), such as CTLA4, PD1 and LAG3, but these approaches have mechanistically focused on the elicitation of anti-tumor responses. However, enhanced inflammation in the TME could also play a detrimental role by facilitating the recruitment, stability and function of Treg cells by up-regulating chemokines that promote Treg cell migration, and/or increasing inhibitory cytokine production. Furthermore, IR blockade may enhance Treg cell function and survival, thereby serving as a resistance mechanism against effective immunotherapy. Given that Treg cells are comprised of functionally and phenotypically heterogeneous sub-populations that may alter their characteristics in a context-dependent manner, it is critical to identify unique molecular pathways that are preferentially used by intratumoral Treg cells. In this review, we discuss markers that serve to identify certain Treg cell subsets, distinguished by chemokine receptors, IRs and cytokines that facilitate their migration, stability and function in the TME. We also discuss how these Treg cell subsets correlate with the clinical outcome of patients with various types of cancer and how they may serve as potential TME-specific targets for novel cancer immunotherapies.
调节性 T (Treg) 细胞通过多种免疫调节机制在维持自身耐受和免疫反应的解决中发挥着关键作用。然而，Treg 细胞容易浸润到肿瘤微环境 (TME) 中，并抑制抗肿瘤免疫反应，从而成为有效癌症免疫治疗的障碍。针对各种抑制性受体 (IR) 的新型免疫疗法的开发已经取得了实质性的进展，例如 CTLA4、PD1 和 LAG3，但这些方法在机制上侧重于引发抗肿瘤反应。然而，TME 中的炎症增强也可能通过上调促进 Treg 细胞迁移的趋化因子，或增加抑制性细胞因子的产生，从而促进 Treg 细胞的募集、稳定和功能，从而产生有害作用。此外，IR 阻断可能增强 Treg 细胞的功能和存活，从而成为有效免疫治疗的抵抗机制。鉴于 Treg 细胞由功能和表型上具有异质性的亚群组成，它们的特征可能会以依赖于上下文的方式发生改变，因此识别优先被肿瘤内 Treg 细胞使用的独特分子途径至关重要。在这篇综述中，我们讨论了用于识别某些 Treg 细胞亚群的标记物，这些亚群通过趋化因子受体、IR 和细胞因子来区分，这些标记物促进了它们在 TME 中的迁移、稳定和功能。我们还讨论了这些 Treg 细胞亚群与各种类型癌症患者的临床结果的相关性，以及它们如何成为新型癌症免疫疗法中潜在的 TME 特异性靶点。
