Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
Medical oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India.
Mol Cancer Res. 2020 Apr;18(4):657-668. doi: 10.1158/1541-7786.MCR-19-0894. Epub 2020 Jan 29.
Immune dysfunction is critical in pathogenesis of cutaneous T-cell lymphoma (CTCL). Few studies have reported abnormal cytokine profile and dysregulated T-cell functions during the onset and progression of certain types of lymphoma. However, the presence of IL9-producing Th9 cells and their role in tumor cell metabolism and survival remain unexplored. With this clinical study, we performed multidimensional blood endotyping of CTCL patients before and after standard photo/chemotherapy and revealed distinct immune hallmarks of the disease. Importantly, there was a higher frequency of "skin homing" Th9 cells in CTCL patients with early (T1 and T2) and advanced-stage disease (T3 and T4). However, advanced-stage CTCL patients had severely impaired frequency of skin-homing Th1 and Th17 cells, indicating attenuated immunity. Treatment of CTCL patients with standard photo/chemotherapy decreased the skin-homing Th9 cells and increased the Th1 and Th17 cells. Interestingly, T cells of CTCL patients express IL9 receptor (IL9R), and there was negligible IL9R expression on T cells of healthy donors. Mechanistically, IL9/IL9R interaction on CD3 T cells of CTCL patients and Jurkat cells reduced oxidative stress, lactic acidosis, and apoptosis and ultimately increased their survival. In conclusion, coexpression of IL9 and IL9R on T cells in CTCL patients indicates the autocrine-positive feedback loop of Th9 axis in promoting the survival of malignant T cells by reducing the oxidative stress. IMPLICATIONS: The critical role of Th9 axis in CTCL pathogenesis indicates that strategies targeting Th9 cells might harbor significant potential in developing robust CTCL therapy.
免疫功能障碍在皮肤 T 细胞淋巴瘤 (CTCL) 的发病机制中起着关键作用。少数研究报告了在某些类型淋巴瘤的发病和进展过程中异常的细胞因子谱和失调的 T 细胞功能。然而，IL9 产生的 Th9 细胞的存在及其在肿瘤细胞代谢和存活中的作用仍未被探索。通过这项临床研究，我们对接受标准光/化疗前后的 CTCL 患者进行了多维血液分型，并揭示了该疾病的独特免疫特征。重要的是，在早期（T1 和 T2）和晚期（T3 和 T4）疾病的 CTCL 患者中，存在更高频率的“皮肤归巢”Th9 细胞。然而，晚期 CTCL 患者的皮肤归巢 Th1 和 Th17 细胞频率严重受损，表明免疫力减弱。对 CTCL 患者进行标准光/化疗治疗可减少皮肤归巢 Th9 细胞并增加 Th1 和 Th17 细胞。有趣的是，CTCL 患者的 T 细胞表达 IL9 受体（IL9R），而健康供体的 T 细胞几乎没有 IL9R 表达。从机制上讲，CTCL 患者的 CD3 T 细胞和 Jurkat 细胞上的 IL9/IL9R 相互作用可降低氧化应激、乳酸酸中毒和细胞凋亡，最终增加细胞存活。总之，CTCL 患者 T 细胞上 IL9 和 IL9R 的共表达表明 Th9 轴的自分泌正反馈回路通过降低氧化应激来促进恶性 T 细胞的存活。结论：Th9 轴在 CTCL 发病机制中的关键作用表明，靶向 Th9 细胞的策略可能在开发强大的 CTCL 治疗方法方面具有重要潜力。
