Department of Immunology, School of Medicine, Aja University of Medical Sciences, Tehran, Iran.
Department of Infectious Diseases, School of Medicine, Aja University of Medical Sciences, Tehran, Iran.
J Cell Physiol. 2020 Dec;235(12):9457-9463. doi: 10.1002/jcp.29750. Epub 2020 May 13.
Colon cancer is one the most common diagnosed cancers in America and Europe. Signal transducer and activator of transcription 3 (STAT3) in colon cancer is associated with proliferation of the tumor cells and suppression of immune responses. STAT3 activation upregulates the transcription of many suppressor genes, including programmed death-ligand 1 (PD-L1). This study was aimed to investigate the effect of STAT3 inhibition in a colon cancer cell line, HCT-15, and particularly in presence of samples obtained from the patients suffering from colon cancer. In this project, the expression of PD-L1 and apoptosis-related proteins were assessed following STAT3 inhibition, using FLLL32, in HCT-15 cells. To evaluate the effects of STAT3 inhibition on immune response, lymphocytes from 20 men with Stage III colon cancer and 20 healthy donors were cocultured with HCT-15 cells in presence or absence of STAT3 inhibitor. Then, T regulatory (T-reg) cell evaluation and intracellular cytokine staining (ICS) were performed using flowcytometry to assess the T-reg and T helper (Th) subset cytokines following STAT3 inhibition. STAT3 inhibition suppressed PD-L1 expression and induced apoptosis in HCT-15 cells. The population of T-reg cells in patients with colon cancer significantly decreased after treatment with STAT3 inhibitor. ICS revealed that STAT3 inhibition promotes Th1 protective immune responses. These findings suggest that STAT3 inhibition through either induction of apoptosis in the colon cancer cells and/or activation of efficient immune responses can lead to overcome cancer-induced immune tolerance.
结直肠癌是美国和欧洲最常见的诊断癌症之一。结直肠癌中的信号转导子和转录激活子 3（STAT3）与肿瘤细胞的增殖和免疫反应的抑制有关。STAT3 的激活上调了许多抑制基因的转录，包括程序性死亡配体 1（PD-L1）。本研究旨在研究 STAT3 抑制在结直肠癌细胞系 HCT-15 中的作用，特别是在患有结直肠癌的患者样本存在的情况下。在这个项目中，使用 FLLL32 评估了 STAT3 抑制后 HCT-15 细胞中 PD-L1 和凋亡相关蛋白的表达。为了评估 STAT3 抑制对免疫反应的影响，将来自 20 名 III 期结肠癌男性患者和 20 名健康供体的淋巴细胞与 HCT-15 细胞共培养，存在或不存在 STAT3 抑制剂。然后，使用流式细胞术进行 T 调节（T-reg）细胞评估和细胞内细胞因子染色（ICS），以评估 STAT3 抑制后 T-reg 和 T 辅助（Th）亚群细胞因子。STAT3 抑制抑制了 HCT-15 细胞中 PD-L1 的表达并诱导了细胞凋亡。结肠癌患者的 T-reg 细胞群体在用 STAT3 抑制剂治疗后显著减少。ICS 显示 STAT3 抑制促进了 Th1 保护性免疫反应。这些发现表明，通过诱导结直肠癌细胞凋亡和/或激活有效的免疫反应来抑制 STAT3 可能导致克服癌症诱导的免疫耐受。
