Protein Phosphatase 2A (PP2A) is essential for CD8+ T cell mediated anti-tumor immunity

Abstract

Abstract PP2A controls a wide variety of cellular pathways responsible for proliferation, growth, differentiation, and apoptosis. However, its role in immune cells, particularly in CD8+ T cells, still remains a mystery. We therefore sought to characterize the influence of PP2A on CD8+ T cell function in anti-tumor response. T cell specific genetic ablation of PP2A in mouse resulted in aberrant anti-tumor activity evidenced by higher tumor volume in both skin melanoma B16F10 and lymphoma E.G7 tumor graft model. Similarly, inhibition of PP2A using small molecule inhibitor LB100 showed similar effect. In addition, lower expression of effector cytokines including IFN-g, TNF-a and Granzyme B was also observed in PP2A-deleted CD8+ T Cells isolated from tumor infiltrate. Importantly, the defect in anti-tumor response is due to deficiency in CD8+ T cell function, which was proven in adoptive transfer experiment, in which CD8+ T cells from both WT and PP2A KO mice into tumor bearing RAG1 KO mice. PP2A KO CD8+ T cells-transferred mice show markedly impaired anti-tumor response. Further mechanism study suggested a possible role of PP2A in regulating CD28 signaling. PP2A KO lead to lower AKT phosphorylation upon CD28 stimulation, along with lower proliferative capability of CD8+ T cells upon stimulation with anti-CD28 and suboptimal anti-CD3 concentration. Thus this study highlights the potentially important role of PP2A in CD8+ T cells and its therapeutic consideration for designing combinatorial immunotherapy.