Priming of naive CD8+ T cells in the presence of IL-12 selectively enhances the survival of CD8 super(+)CD62L super(hi) cells and results in superior anti-tumor activity in a tolerogenic murine model

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2008-04, Vol.57 (4), p.563-572
• Main Authors: Diaz-Montero, C M, El Naggar, S, Al Khami, A, El Naggar, R, Montero, A J, Cole, D J, Salem, M L
• Format: Article
• Language: English
• ISSN: 0340-7004
• DOI: 10.1007/s00262-007-0394-0

During the antigen-dependant activation process several subsets CD8 super(+) 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 super(+)T (CD62L super(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 naive CD8 super(+) T cells in the presence of IL-12 selectively rescued early CD8 super(+) CD62L super(hi) from activation induced cell death and resulted in the increased accumulation of this subset of CD8 super(+) T cells. Furthermore, we demonstrated that IL-12 directly modulated the expression of CD62L on activated CD8 super(+) T cells. When used for ACT, naive CD8 super(+) 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 naive CD8 super(+) T cells with IL-12 prior to ACT could significantly enhance their anti-tumor activity.