During the antigen-dependant activation process several subsets CD8 + T cells appear with different phenotypic and functional characteristics. Recent studies indicate that the state of T cell differentiation radically affects their ability to effectively respond to tumor challenge, with early effector CD8 + T (CD62L high ) cells having better anti-tumor activity. Thus strategies aimed at optimizing the generation of such subpopulations could significantly enhance the effectiveness of adoptive cell therapy (ACT) for cancer. In this study, we show that priming of naïve CD8 + T cells in the presence of IL-12 selectively rescued early CD8 + CD62L hi from activation induced cell death and resulted in the increased accumulation of this subset of CD8 + T cells. Furthermore, we demonstrated that IL-12 directly modulated the expression of CD62L on activated CD8 + T cells. When used for ACT, naïve CD8 + T cells primed in vitro in the presence of IL-12 showed superior anti-tumor activity toward B16 melanoma. Importantly, using the Pmel-1 model, priming pmel-1 cells in vitro with IL-12 reduced the state of functional tolerance associated with the non-mutated "self" tumor antigen gp100, as demonstrated by significant tumor responses in the absence of vaccination. Together, our results suggest that in vitro conditioning of naïve CD8 + T cells with IL-12 prior to ACT could significantly enhance their anti-tumor activity.