title: 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.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637; and.
authors.forename: César
authors.identifier: http://orcid.org/0000-0002-2281-1045
authors.initials: C
authors.lastname: Evaristo
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637.
authors.forename: Stefani
authors.identifier: http://orcid.org/0000-0003-3257-4546
authors.initials: S
authors.lastname: Spranger
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637; and.
authors.forename: Sarah E
authors.identifier: http://orcid.org/0000-0001-5047-2549
authors.initials: SE
authors.lastname: Barnes
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637; and.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Miller
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637; and.
authors.forename: Luciana L
authors.identifier: http://orcid.org/0000-0001-5866-5214
authors.initials: LL
authors.lastname: Molinero
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637; and.
authors.forename: Frederick L
authors.identifier: http://orcid.org/0000-0001-9063-6691
authors.initials: FL
authors.lastname: Locke
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637; and Department of Pathology, University of Chicago, Chicago, IL 60637.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637; and malegre@midway.uchicago.edu.
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Alegre
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D015870:Gene Expression; D005818:Genetic Engineering / Q000379:methods; D064593:Heterografts; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics* / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology
chemical_list: D016328:NF-kappa B; D007371:Interferon-gamma; D051550:I-kappa B Kinase