Cutting Edge: Engineering Active IKKβ in T Cells Drives Tumor Rejection

Acquired dysfunction of tumor-reactive T cells is one mechanism by which tumors can evade the immune system. Identifying and correcting pathways that contribute to such dysfunction should enable novel anticancer therapy design. During cancer growth, T cells show reduced NF-kappa B activity, which is required for tumor rejection. Impaired T cell-intrinsic NF-kappa B may create a vicious cycle conducive to tumor progression and further T cell dysfunction. We hypothesized that forcing T cell-intrinsic NF-kappa B activation might break this cycle and induce tumor elimination. NF-kappa B was activated in T cells by inducing the expression of a constitutively active form of the upstream activator I kappa B kinase beta (IK kappa beta). T cell-restricted constitutively active IK kappa beta augmented the frequency of functional tumor-specific CD8(+) T cells and improved tumor control. Transfer of constitutively active IK kappa B-transduced T cells also boosted endogenous T cell responses that controlled pre-established tumors. Our results demonstrate that driving T cell-intrinsic NF-kappa B can result in tumor control, thus identifying a pathway with potential clinical applicability.