Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
J Immunol. 2022 Aug 1;209(3):621-628. doi: 10.4049/jimmunol.2200041. Epub 2022 Jul 13.
We had shown previously that the protein phosphatase 2A regulatory subunit PPP2R2D suppresses IL-2 production, and PPP2R2D deficiency in T cells potentiates the suppressive function of regulatory T (Treg) cells and alleviates imiquimod-induced lupus-like pathology. In this study, in a melanoma xenograft model, we noted that the tumor grew in larger sizes in mice lacking PPP2R2D in T cells (LckR2D) compared with wild type (R2D) mice. The numbers of intratumoral T cells in LckR2D mice were reduced compared with R2D mice, and they expressed a PD-1CD3CD44 exhaustion phenotype. In vitro experiments confirmed that the chromatin of exhaustion markers PD-1, LAG3, TIM3, and CTLA4 remained open in LckR2D CD4 T conventional compared with R2D T conventional cells. Moreover, the percentage of Treg cells (CD3CD4Foxp3CD25) was significantly increased in the xenografted tumor of LckR2D mice compared with R2D mice probably because of the increase in the percentage of IL-2-producing LckR2D T cells. Moreover, using adoptive T cell transfer in mice xenografted with melanoma, we demonstrated that PPP2R2D deficiency in T cells enhanced the inhibitory effect of Treg cells in antitumor immunity. At the translational level, analysis of publicly available data from 418 patients with melanoma revealed that PPP2R2D expression levels correlated positively with tumor-infiltration level of CD4 and CD8 T cells. The data demonstrate that PPP2R2D is a negative regulator of immune checkpoint receptors, and its absence exacerbates effector T cell exhaustion and promotes Treg cell expansion. We conclude that PPP2R2D protects against melanoma growth, and PPP2R2D-promoting regimens can have therapeutic value in patients with melanoma.
我们之前曾表明，蛋白磷酸酶 2A 调节亚基 PPP2R2D 抑制 IL-2 的产生，并且 T 细胞中 PPP2R2D 的缺失增强了调节性 T（Treg）细胞的抑制功能，并减轻了咪喹莫特诱导的狼疮样病理。在这项研究中，在黑色素瘤异种移植模型中，我们注意到与野生型（R2D）小鼠相比，缺乏 T 细胞（LckR2D）中 PPP2R2D 的小鼠肿瘤生长得更大。与 R2D 小鼠相比，LckR2D 小鼠肿瘤内 T 细胞的数量减少，并且它们表达 PD-1CD3CD44 耗竭表型。体外实验证实，与 R2D T 常规细胞相比，LckR2D CD4 T 常规细胞中耗竭标志物 PD-1、LAG3、TIM3 和 CTLA4 的染色质保持开放。此外，与 R2D 小鼠相比，LckR2D 小鼠的异种移植肿瘤中 Treg 细胞（CD3CD4Foxp3CD25）的比例显著增加，可能是由于产生 IL-2 的 LckR2D T 细胞的比例增加所致。此外，在黑色素瘤异种移植的小鼠中通过过继性 T 细胞转移，我们证明了 T 细胞中 PPP2R2D 的缺失增强了 Treg 细胞在抗肿瘤免疫中的抑制作用。在转化水平上，对 418 名黑色素瘤患者的公开可用数据进行分析表明，PPP2R2D 的表达水平与 CD4 和 CD8 T 细胞浸润肿瘤的水平呈正相关。这些数据表明 PPP2R2D 是免疫检查点受体的负调节剂，其缺失会加剧效应 T 细胞耗竭并促进 Treg 细胞扩增。我们得出结论，PPP2R2D 可防止黑色素瘤生长，并且 PPP2R2D 促进的方案在黑色素瘤患者中具有治疗价值。
