Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, 77843, USA.
Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, 77843, USA.
Cancer Immunol Immunother. 2023 Dec;72(12):3985-3999. doi: 10.1007/s00262-023-03530-3. Epub 2023 Oct 17.
There is evidence that the orphan nuclear receptor 4A1 (NR4A1, Nur77) is overexpressed in exhausted CD8 + T cells and regulates PD-L1 in tumors. This study investigated the effects of potent bis-indole-derived NR4A1 antagonists on reversing T-cell exhaustion and downregulating PD-L1 in colon tumors/cells. NR4A1 antagonists inhibited colon tumor growth and downregulated expression of PD-L1 in mouse colon MC-38-derived tumors and cells. TILs from MC-38 cell-derived colon tumors and splenic lymphocytes exhibited high levels of the T-cell exhaustion markers including PD-1, 2B4, TIM3+ and TIGIT and similar results were observed in the spleen, and these were inhibited by NR4A1 antagonists. In addition, treatment with NR4A1 antagonists induced cytokine activation markers interferon γ, granzyme B and perforin mRNAs and decreased TOX, TOX2 and NFAT in TIL-derived CD8 + T cells. Thus, NR4A1 antagonists decrease NR4A1-dependent pro-oncogenic activity and PD-L1 expression in colon tumors and inhibit NR4A1-dependent T-cell exhaustion in TILs and spleen and represent a novel class of mechanism-based drugs that enhance immune surveillance in tumors.
有证据表明，孤儿核受体 4A1（NR4A1，Nur77）在耗尽的 CD8+T 细胞中过度表达，并调节肿瘤中的 PD-L1。本研究探讨了强效双吲哚衍生的 NR4A1 拮抗剂对逆转 T 细胞耗竭和下调结肠肿瘤/细胞中 PD-L1 的影响。NR4A1 拮抗剂抑制了源自小鼠结肠 MC-38 的肿瘤和细胞中结肠肿瘤的生长，并下调了 PD-L1 的表达。源自 MC-38 细胞的结肠肿瘤和脾淋巴细胞中的 TIL 表现出高水平的 T 细胞耗竭标志物，包括 PD-1、2B4、TIM3+和 TIGIT，并且在脾脏中观察到类似的结果，这些结果可被 NR4A1 拮抗剂抑制。此外，NR4A1 拮抗剂处理诱导细胞因子激活标志物干扰素 γ、颗粒酶 B 和穿孔素 mRNAs 的表达，并降低 TIL 衍生的 CD8+T 细胞中的 TOX、TOX2 和 NFAT。因此，NR4A1 拮抗剂降低了 NR4A1 依赖性致癌活性和结肠肿瘤中的 PD-L1 表达，并抑制了 TIL 和脾脏中 NR4A1 依赖性 T 细胞耗竭，代表了一类增强肿瘤免疫监视的新型机制药物。
