Department of Physiological Chemistry, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
Department of Immunology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
Sci Rep. 2018 Apr 19;8(1):6283. doi: 10.1038/s41598-018-24512-x.
Two major phospholipase D (PLD) isozymes in mammals, PLD1 and PLD2, hydrolyze the membrane phospholipid phosphatidylcholine to choline and the lipid messenger phosphatidic acid. Although their roles in cancer cells have been well studied, their functions in tumor microenvironment have not yet been clarified. Here, we demonstrate that PLD2 in cytotoxic CD8 T cells plays a crucial role in anti-tumor immunity by regulating their cell proliferation. We found that growth of tumors formed by subcutaneously transplanted cancer cells is enhanced in Pld2-knockout mice. Interestingly, this phenotype was found to be at least in part attributable to the ablation of Pld2 from bone marrow cells. The number of CD8 T cells, which induce cancer cell death, significantly decreased in the tumor produced in Pld2-knockout mice. In addition, CD3/CD28-stimulated proliferation of primary cultured splenic CD8 T cells is markedly suppressed by Pld2 ablation. Finally, CD3/CD28-dependent activation of Erk1/2 and Ras is inhibited in Pld2-deleted CD8 T cells. Collectively, these results indicate that PLD2 in CD8 T cells plays a key role in their proliferation through activation of the Ras/Erk signaling pathway, thereby regulating anti-tumor immunity.
两种主要的哺乳动物磷脂酶 D（PLD）同工酶，PLD1 和 PLD2，将细胞膜磷脂酰胆碱水解为胆碱和脂质信使磷脂酸。尽管它们在癌细胞中的作用已得到充分研究，但它们在肿瘤微环境中的功能尚未阐明。在这里，我们证明细胞毒性 CD8 T 细胞中的 PLD2 通过调节其细胞增殖在抗肿瘤免疫中发挥关键作用。我们发现，皮下移植癌细胞形成的肿瘤在 Pld2 敲除小鼠中生长增强。有趣的是，这种表型至少部分归因于骨髓细胞中 Pld2 的消融。诱导癌细胞死亡的 CD8 T 细胞数量在 Pld2 敲除小鼠产生的肿瘤中显著减少。此外，Pld2 消融明显抑制了原代培养的脾 CD8 T 细胞中 CD3/CD28 刺激的增殖。最后，Pld2 缺失的 CD8 T 细胞中 Ras/Erk 信号通路的激活被抑制。总之，这些结果表明，CD8 T 细胞中的 PLD2 通过激活 Ras/Erk 信号通路在其增殖中发挥关键作用，从而调节抗肿瘤免疫。
