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.

中文翻译：

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磷脂酶D2在抗肿瘤免疫中的生理功能：调节CD8 + T淋巴细胞的增殖。

哺乳动物中的两种主要磷脂酶D（PLD）同工酶PLD1和PLD2将膜磷脂磷脂酰胆碱水解为胆碱和脂质使者磷脂酸。尽管已经充分研究了它们在癌细胞中的作用，但尚未阐明它们在肿瘤微环境中的功能。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起着至关重要的作用。我们发现由皮下移植的癌细胞形成的肿瘤的生长在Pld2基因敲除小鼠中得到增强。有趣的是，发现该表型至少部分归因于来自骨髓细胞的Pld2的消融。CD8 ⁺的数量诱导癌细胞死亡的T细胞在Pld2基因敲除小鼠中产生的肿瘤中显着减少。此外，Pld2消融可显着抑制CD3 / CD28刺激的原代培养脾脏CD8 ⁺ T细胞的增殖。最后，CD3 / CD28依赖的Erk1 / 2和Ras激活在Pld2缺失的CD8 ⁺ T细胞中受到抑制。总体而言，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起关键作用，从而调节抗肿瘤免疫力。