Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR 999078, China.
Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD, USA; Department of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin 130117, China.
Int Immunopharmacol. 2021 Dec;101(Pt A):108345. doi: 10.1016/j.intimp.2021.108345. Epub 2021 Nov 15.
Immunosuppressive CD4Foxp3 regulatory T cells (Tregs) promote tumor immune evasion and thus targeting of Tregs has become an strategy in cancer immunotherapy. Tumor necrosis factor receptor 2 (TNFR2) is highly expressed and important for the immunosuppressive function of Tregs in humans and mice. Thus, the benefit of targeting TNFR2 in cancer immunotherapy merits more investigation. A previous report identified a new murine monoclonal anti-TNFR2 antibody (designated TY101), which showed therapeutic efficacy in murine cancer models, but its mechanism of action was less understood. In this study, the capacity of a combination of immunostimulants to enhance the effect of this inhibitor of Tregs was investigated. We examined the efficacy of TY101 as an anti-tumor immune reagent combined with HMGN1 (N1, a dendritic cell activating TLR4 agonist) and R848 (a synthetic TLR7/8 agonist). This immunotherapeutic combination exerted synergistic antitumor effects as compared with any single treatment. The antitumor response was mainly mediated by the depletion of Tregs and stimulation of cytotoxic CD8 T cell activation. The result also suggested that the effect of TY101 was similar to that of anti-PD-L1 when used in combination with these immunostimulants. Therefore, we propose that treatment strategies of antagonizing TNFR2 on Tregs would behave as potent checkpoint inhibitors and can potentially be utilized to develop a novel antitumor immunotherapy.
抑制性 CD4Foxp3 调节性 T 细胞（Tregs）促进肿瘤免疫逃逸，因此针对 Tregs 已成为癌症免疫治疗的一种策略。肿瘤坏死因子受体 2（TNFR2）在人类和小鼠的 Tregs 免疫抑制功能中高度表达且至关重要。因此，针对 TNFR2 在癌症免疫治疗中的益处值得更深入的研究。先前的一份报告鉴定了一种新型的小鼠单克隆抗 TNFR2 抗体（命名为 TY101），该抗体在小鼠癌症模型中显示出治疗功效，但对其作用机制的了解较少。在这项研究中，研究了免疫刺激剂的组合增强这种 Tregs 抑制剂作用的能力。我们研究了 TY101 作为抗肿瘤免疫试剂与 HMGN1（N1，一种树突状细胞激活 TLR4 激动剂）和 R848（一种合成 TLR7/8 激动剂）联合使用的效果。与任何单一治疗相比，这种免疫治疗联合具有协同的抗肿瘤作用。抗肿瘤反应主要是通过 Tregs 的耗竭和细胞毒性 CD8 T 细胞激活的刺激介导的。结果还表明，当与这些免疫刺激剂联合使用时，TY101 的作用类似于抗 PD-L1。因此，我们提出针对 Tregs 上的 TNFR2 的治疗策略将表现为有效的检查点抑制剂，并有可能被用于开发新的抗肿瘤免疫疗法。
