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

Abstract

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-κB activity, which is required for tumor rejection. Impaired T cell–intrinsic NF-κB may create a vicious cycle conducive to tumor progression and further T cell dysfunction. We hypothesized that forcing T cell–intrinsic NF-κB activation might break this cycle and induce tumor elimination. NF-κB was activated in T cells by inducing the expression of a constitutively active form of the upstream activator IκB kinase β (IKKβ). T cell–restricted constitutively active IKKβ augmented the frequency of functional tumor-specific CD8+ T cells and improved tumor control. Transfer of constitutively active IKKβ–transduced T cells also boosted endogenous T cell responses that controlled pre-established tumors. Our results demonstrate that driving T cell–intrinsic NF-κB can result in tumor control, thus identifying a pathway with potential clinical applicability.