The atypical IκB factor IκBδ enhances CD8 T cell accumulation and effector functions in solid tumors.

Two prominent mechanisms by which tumors fend off immune control are by constraining the ability of T cells and CAR T cells to survive and expand in the tumor, and by restraining their ability to sustain full cytotoxic capacity. We identified IκBδ, encoded by Nfkbid, a poorly characterized IκB family member, as a molecular lever that overcomes both of these constraints on anti-tumor CD8+ tumor-infiltrating lymphocytes (TILs). Nfkbid is an NFAT target gene that is expressed in CD8+ effector T cells and, at modest levels, in CD8+ TILs. We found that Nfkbid depletion impaired TIL accumulation, exacerbating the growth of solid tumors. On the other hand, ectopic IκBδ overexpression enhanced TIL expansion, reduced the expression of exhaustion-associated transcription factors and inhibitory receptors, and elevated cytotoxic molecule production, leading to enhanced tumor control. IκBδ has a shorter protein isoform that is identical in a core region spanning the ankyrin-repeat domain known to interact with NFκB proteins, but that lacks the ~150-residue N-terminal region. We showed that the shared core region is sufficient to drive T cell accumulation, whereas the N-terminal peptide region is required for robust effector function and to counter exhaustion, underscoring that tumor-infiltrating CD8+ T cell accumulation and effector differentiation are separable programs. Our current study provides evidence that IκBδ, an atypical member of the NFκB family, is a lever to overcome two cardinal deficits that limit CD8+ TIL anti-tumor efficacy: impaired accumulation in the tumor and diminished effector function.