Hu Liangchang, Zhao Yu, Zhang Xuguang, Ma Chunhui
Department of Oncology, Affiliated Hospital of Shandong Second Medical University, Weifang, China.
School of Medical Laboratory, Shandong Second Medical University, Weifang, China.
Cancer Med. 2025 Jan;14(1):e70147. doi: 10.1002/cam4.70147.
Activin A, a noteworthy member of the TGF-β superfamily. Activin A can regulate the biological functions of various immune cells, such as macrophages, neutrophils, NK cells, etc. The purpose of this study is to investigate the regulatory effect and related mechanisms of activin A on CD8 T cells.
This study established a mouse subcutaneous transplantation model of hepatoma to explore whether activin A has a regulatory effect of CD8 T cells. And reveal the biological characteristics of ActRIIA high CD8 T cells.
We discovered that CD8 T cells express ActRIIA, ActRIIB, and Smad2,3,4. Unlike high-dose activin A, low-dose activin A increased the content of CD8 T cells while also suppressing tumor growth. In addition, low-dose activin A promoted expression of perforin, granzyme B, CD69, CD11c, CD49b, Ki67 and ActRIIA in CD8 T cells. And the results indicated that high-dose activin A promotes the expression of PPM1A in T cells, while low-dose activin A has no effect on these cells. The tumor contained more ActRIIA high CD8 T cells compared to the peripheral blood and spleen. ActRIIA high CD8 T cells highly express cytotoxic molecules and cytokines. And ActRIIA high CD8 T cells not only expressed high levels of activation/co-stimulatory markers CD69, CD278, and CD28, but also high levels of inhibitory markers CD366 and KLRG1. Different chemokine receptors displayed varying levels of expression in ActRIIA high CD8 T cells. Additionally, these cells have a high proliferative potential. Finally, overexpression of Mettl3 inhibited the expression of ActRIIA in CD8 T cells.
This study demonstrated that low-dose activin A enhanced the anti-tumor effect of CD8 T cells, and ActRIIA high CD8 T cells actively contribute to tumor immunity.
激活素A是转化生长因子-β超家族中一个值得关注的成员。激活素A可调节多种免疫细胞的生物学功能，如巨噬细胞、中性粒细胞、自然杀伤细胞等。本研究旨在探讨激活素A对CD8 T细胞的调节作用及相关机制。
本研究建立了小鼠肝癌皮下移植模型，以探讨激活素A是否对CD8 T细胞具有调节作用。并揭示ActRIIA高表达的CD8 T细胞的生物学特性。
我们发现CD8 T细胞表达ActRIIA、ActRIIB和Smad2、3、4。与高剂量激活素A不同，低剂量激活素A在增加CD8 T细胞含量的同时还抑制肿瘤生长。此外，低剂量激活素A促进CD8 T细胞中穿孔素、颗粒酶B、CD69、CD11c、CD49b、Ki67和ActRIIA的表达。结果表明，高剂量激活素A促进T细胞中PPM1A的表达，而低剂量激活素A对这些细胞无影响。与外周血和脾脏相比，肿瘤中含有更多ActRIIA高表达的CD8 T细胞。ActRIIA高表达的CD8 T细胞高表达细胞毒性分子和细胞因子。并且ActRIIA高表达的CD8 T细胞不仅高水平表达激活/共刺激标志物CD69、CD278和CD28，还高水平表达抑制标志物CD366和KLRG1。不同的趋化因子受体在ActRIIA高表达的CD8 T细胞中表现出不同水平的表达。此外，这些细胞具有较高的增殖潜力。最后，Mettl3的过表达抑制了CD8 T细胞中ActRIIA的表达。
本研究表明低剂量激活素A增强了CD8 T细胞的抗肿瘤作用，且ActRIIA高表达的CD8 T细胞对肿瘤免疫有积极贡献。
