Dual protein phosphatase promotes effector CD8+ T-cell persistence and tumor control 2241571

Abstract

CD8+ T cell persistence is essential for long-term protection against cancer and infection. Immune checkpoint inhibitors improve cancer outcomes but still fail to sustain CD8+ T cell function under chronic antigen exposure. Kinases are well established in T cell-mediated tumor immunity, whereas protein phosphatases remain relatively unexplored. Here, we identify a dual protein phosphatase (DPP) that acts as a regulator of effector CD8+ T cell differentiation and persistence in tumor models. DPP expression was higher in effector memory CD8+ T cells than in naïve-like and exhausted subsets across three cancer types. DPP deletion in CD8+ T cells reduced the maintenance of effector CD8+ T cells and impaired memory formation of CD8+ T cells after OVA vaccination, resulting in poor long-term tumor protection. Mechanistically, DPP deficiency in CD8+ T cells upregulated PI3K-AKT signaling and diminished FoxO1 activity, thereby limiting memory-like properties while promoting exhaustion and apoptosis. DPP expression was higher in effector memory CD8+ T cells than in naïve-like and exhausted subsets across three cancer types. DPP deletion in CD8+ T cells reduced the maintenance of effector CD8+ T cells and impaired memory formation of CD8+ T cells after OVA vaccination, resulting in poor long-term tumor protection. Mechanistically, DPP deficiency in CD8+ T cells upregulated PI3K-AKT signaling and diminished FoxO1 activity, thereby limiting memory-like properties while promoting exhaustion and apoptosis. Our findings establish DPP as a novel regulator of CD8+ T cell persistence and memory formation, providing a strategy to improve the durability of cancer immunotherapy. NRF-2022R1A2B5B03001431 Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)