Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.
Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.
Cancer Lett. 2019 Aug 10;457:168-179. doi: 10.1016/j.canlet.2019.05.003. Epub 2019 May 9.
T Regulatory cells (Tregs) act as a double-edged sword by regulating immune homeostasis (protective role) and inhibiting immune responses in different disease settings (pathological role). They contribute to cancer development and progression by suppressing T effector cell (Teff) functions. Decreased ratios of intratumoral CD8 T cells to Tregs have been associated with poor prognosis in most cancer types. Targeting immune checkpoints (ICs), such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1), by immune checkpoint inhibitors (ICIs) in cancer patients has been beneficial in inducing anti-tumor immune responses and improving clinical outcomes. However, response rates remain relatively low, ranging from 15 to 40% depending on cancer type. Additionally, a significant proportion of patients who initially demonstrates a clinical response can acquire resistance overtime. This acquired resistance could occur due to the emergence of compensatory mechanisms within the tumor microenvironment (TME) to evade the anti-tumor effects of ICIs. In this review, we describe the immunosuppressive role of Tregs in the TME, the effects of currently approved ICIs on Treg phenotype and function, and the mechanisms of acquired resistance to ICIs mediated by Tregs within the TME, such as the over-expression of ICs, the up-regulation of immunosuppressive molecules, and apoptotic Treg-induced immunosuppression. We also describe potential therapeutic strategies to target Tregs in combination with ICIs aiming to overcome such resistance and improve clinical outcomes. Elucidating the Treg-mediated acquired resistance mechanisms should benefit the designing of well-targeted therapeutic strategies to overcome resistance and maximize the therapeutic efficacy in cancer patients.
调节性 T 细胞（Tregs）在调节免疫稳态（保护作用）和抑制不同疾病环境中的免疫反应（病理作用）方面发挥着双刃剑作用。它们通过抑制 T 效应细胞（Teff）的功能促进癌症的发展和进展。在大多数癌症类型中，肿瘤内 CD8 T 细胞与 Tregs 的比值降低与预后不良相关。在癌症患者中，通过免疫检查点抑制剂（ICIs）靶向免疫检查点（ICs），如细胞毒性 T 淋巴细胞相关抗原-4（CTLA-4）和程序性细胞死亡-1（PD-1），已被证明有助于诱导抗肿瘤免疫反应并改善临床结果。然而，反应率仍然相对较低，根据癌症类型的不同，范围从 15%到 40%不等。此外，相当一部分最初表现出临床反应的患者随着时间的推移会获得耐药性。这种获得性耐药可能是由于肿瘤微环境（TME）内出现补偿机制，从而逃避了 ICI 的抗肿瘤作用。在这篇综述中，我们描述了 Tregs 在 TME 中的免疫抑制作用、目前批准的 ICI 对 Treg 表型和功能的影响，以及 Tregs 在 TME 中介导对 ICI 的获得性耐药的机制，例如 IC 的过度表达、免疫抑制分子的上调和凋亡 Treg 诱导的免疫抑制。我们还描述了潜在的治疗策略，即联合使用 ICI 靶向 Tregs，以克服这种耐药性并改善临床结果。阐明 Treg 介导的获得性耐药机制应有助于设计针对 Tregs 的靶向治疗策略，以克服耐药性并最大限度地提高癌症患者的治疗效果。
