Abstract
Background
The role of co-stimulation in CD4+ T cell activation by professional APC is well established, while less is known of the role co-stimulation plays when CD4+ T cells interact directly with tumor cells.
Methods
Through genetic engineering of human CD4+ T cells, we tested the hypothesis that integration of co-stimulatory signaling domains within a tumor-targeting chimeric Ag receptor (CAR), the IL-13Rα2-specific IL-13-zetakine (IL13ζ), would enhance CD4+ T cell mediated responses against tumors that fail to express ligands for co-stimulatory receptors.
Results
Compared with CD3ζ-mediated activation alone, CD4+ effector T cells expressing the IL13–CD28–41BBζ CAR exhibited augmented/sustained MAPK and AKT activity, up-regulated Th1 cytokine production, and enhanced cytolytic potency against tumor targets. Moreover, upon recursive stimulation with tumor, the IL13–CD28–41BBζ+ cells retained/recycled their lytic function, whereas IL-13ζ+ CD4+ cells became anergic/exhausted. These in vitro observations correlated with enhanced in vivo control of established orthotopic CNS glioma xenografts in immunodeficient mice mediated by adoptively transferred ex vivo-expanded CD4+ T cells expressing the co-stimulatory CAR.
Discussion
Together these studies demonstrate the importance of integrating co-stimulation with CD3ζ signaling events to activate fully CD4+ anti-tumor effector cells for sustained function in the tumor microenvironment.