Data Sheet 1_Ras protein activator-like 3 is a key Ras GTPase-activating protein that protects the survival and anti-tumor activity of CD8+ T cells.pdf

In this study, we identify the leukocyte-specific Ras GTPase-activating protein (RasGAP) RASAL3 as an important regulator of CD8⁺ T cell homeostasis and anti-tumor immunity. Following T cell receptor (TCR) stimulation, RASAL3-deficient CD8⁺ T cells display sustained Ras activation, resulting in increased activation-induced cell death (AICD).

The surviving RASAL3-deficient CD8⁺ T cells exhibit impaired effector functions, including reduced cytokine production and decreased tumor-killing activity. Using an in vivo B16-F10 melanoma model, we found that CD8⁺ T cell-specific RASAL3-deficient mice (R3^fl/flCd8-Cre) develop significantly faster tumor growth compared with control mice. Although Programmed death protein 1 (PD-1) blockade partially restores anti-tumor responses in these mice, the therapeutic effect remains markedly weaker than that observed in control animals.