PPP2R2D Suppresses Effector T Cell Exhaustion and Regulatory T Cell Expansion and Inhibits Tumor Growth in Melanoma

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 (Lck(C)(re)R2D(fl/fl)) compared with wild type (R2D(fl/fl)) mice. The numbers of intratumoral T cells in Lck(Cre)R2D(fl)(/fl) mice were reduced compared with R2D(fl)(/fl) mice, and they expressed a PD-1(+)CD3(+)CD44(+) exhaustion phenotype. In vitro experiments confirmed that the chromatin of exhaustion markers PD-1, LAG3, TIM3, and CTLA4 remained open in Lck(C)(re)R2D(fl/fl) CD4 T conventional compared with R2D(fl/fl) T conventional cells. Moreover, the percentage of Treg cells (CD3(+)CD4(+)Foxp3(+)CD25(hi)) was significantly increased in the xenografted tumor of Lck(C)(re)R2D(fl/fl) mice compared with R2D(fl)(/fl) mice probably because of the increase in the percentage of IL-2-producing Lck(C)(re)R2D(fl/fl) 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.