Department of Endocrinology, Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, Liaoning, China.
Department of Endocrinology, First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning, China.
Dig Dis Sci. 2022 Jun;67(6):2173-2181. doi: 10.1007/s10620-021-07077-0. Epub 2021 Jun 7.
Colon cancer, ranked third in cancer related mortality, is the most common malignant cancer of digestive tract. Though immune checkpoint inhibitors show promising efficacy in colon cancer, a rather high unresponsive rate and recurrence rate requires further elucidation of the underlying regulatory mechanism of cancer-related immunity.
To study the regulatory function of Orexin A in the expression of exosomal PD-L1 and T cell activity.
Orthotopic colon cancer transplantation mice model were established to study the cancer growth and immune infiltration between Orexin A treated group and untreated group. In vitro studies using mouse CT-26 and human HCT-116 colon cancer cell model studied the effect of Orexin A on cellular and exosomal PD-L1 expression. Co-culturing Jurkat cells with exosomes delivered by cancer cells treated with Orexin A, PD-L1 knockdown and PBS studied different effects on T cell. Comparing Orexin A with WP1066, a JAK2/STAT3 inhibitor verified the mechanism of these changes.
The growth rate of orthotopic transplanted colon cancer was slower in Orexin A treated group, with lower PD-L1 expression and higher immune infiltration. Orexin A could inhibit cellular and exosomal PD-L1 expression. The decreased expression of PD-L1 in exosomes could promote the activity of Jurkat cells secreting higher level of IFN-γ and IL-2. Orexin A showed a similar effect like WP1066 which proved JAK2/STAT3 signaling pathway was its downstream signaling pathway.
Orexin A could suppress the expression of exosomal PD-L1 in colon cancer cells and promote T cells activity by inhibiting JAK2/STAT3 signaling pathway.
结肠癌死亡率排名第三，是最常见的消化道恶性肿瘤。免疫检查点抑制剂在结肠癌中显示出良好的疗效，但较高的无应答率和复发率需要进一步阐明癌症相关免疫的潜在调节机制。
研究食欲素 A 在细胞外囊泡 PD-L1 表达和 T 细胞活性中的调节功能。
建立结肠癌原位移植小鼠模型，研究食欲素 A 处理组与未处理组之间的肿瘤生长和免疫浸润情况。使用小鼠 CT-26 和人 HCT-116 结肠癌细胞模型进行体外研究，研究食欲素 A 对细胞和细胞外囊泡 PD-L1 表达的影响。将 Jurkat 细胞与用 Orexin A 处理的癌细胞分泌的外体共培养，进行 PD-L1 敲低和 PBS 对照实验，研究对 T 细胞的不同影响。比较 Orexin A 与 JAK2/STAT3 抑制剂 WP1066，验证这些变化的机制。
食欲素 A 处理组原位移植结肠癌的生长速度较慢，PD-L1 表达较低，免疫浸润较高。食欲素 A 可抑制细胞和细胞外囊泡 PD-L1 的表达。外体中 PD-L1 的表达降低可促进 Jurkat 细胞分泌更高水平的 IFN-γ 和 IL-2。Orexin A 表现出与 WP1066 相似的效果，证明 JAK2/STAT3 信号通路是其下游信号通路。
食欲素 A 可通过抑制 JAK2/STAT3 信号通路，抑制结肠癌细胞中外体 PD-L1 的表达，促进 T 细胞活性。
