p50 suppresses cytotoxic T lymphocyte effector function to regulate tumor immune escape and response to immunotherapy

Abstract

BackgroundNF-κB is a key link between inflammation and cancer. Previous studies of NF-κB have largely focused on tumor cells, and the intrinsic function of NF-κB in T cells in tumor development and response to immunotherapy is largely unknown. We aimed at testing the hypothesis that NF-κB1 (p50) activation in T cells underlies human colon cancer immune escape and human cancer non-response to anti-PD-1 immunotherapy.MethodsWe screened NF-κB activation in human colon carcinoma and used mouse models to determine p50 function in tumor cells and immune cells. RNA-Seq was used to identify p50 target genes. p50 binding to target gene promoters were determined by electrophoresis mobility shift assay and chromatin immunoprecipitation. A p50 activation score was generated from gene expression profiling and used to link p50 activation to T-cell activation and function pre-nivolumab and post-nivolumab immunotherapy in human patients with cancer.Resultsp50 is the dominant form of NF-κB that is highly activated in immune cells in the human colorectal carcinoma microenvironment and neighboring non-neoplastic colon epithelial cells. Tumor cell intrinsic p50 signaling and T-cell intrinsic p50 signaling exert opposing functions in tumor growth control in vivo. Deleting Nfkb1 in tumor cells increased whereas in T cells decreased tumor growth in preclinical mouse models. Gene expression profiling identified Gzmb as a p50 target in T cells. p50 binds directly to a previously uncharacterized κB sequence at the Gzmb promoter in T cells, resulting in repression of Gzmb expression in tumor-infiltrating cytotoxic T lymphocytes (CTLs) to induce a dysfunctional CTL phenotype to promote tumor immune escape. p50 activation is inversely correlated with both GZMB expression and T-cell tumor infiltration in human colorectal carcinoma. Furthermore, nivolumab immunotherapy decreased p50 activation and increased GZMB expression in human patients with melanoma.ConclusionsInflammation activates p50 that binds to the Gzmb promoter to repress granzyme B expression in T cells, resulting in CTL dysfunction to confer tumor immune escape and decreased response to anti-PD-1 immunotherapy.

Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS

“…37 The pronounced immune activation and NFκB upregulation in PTCL-EBV may augment the local inflammatory state, suppress cytotoxic T-lymphocyte effector function resulting in an immunosuppressive TME that enhances immune evasion and aggressive behavior. 38,39 While CD27 normally activates NFκB, promotes cell survival and enhances T-and B-cell receptor-mediated proliferative signals, dysregulation of CD27 signaling can result in T-cell exhaustion and dysfunction 40,41 . Interestingly, we found EBV-miRNAs to be predominantly downregulated in PTCL-EBV compared to ENKTL and this may further contribute to the inflammatory state with overexpression of immune-related genes.…”

G6PD functions as a metabolic checkpoint to regulate granzyme B expression in tumor-specific cytotoxic T lymphocytes

“…ChIP was performed as previously described 22 using anti-H3K9me3 (Abcam, Cambridge, Massachusetts, USA), or anti-H3K9ac (Cell Signaling Transduction) antibodies and the ChIP Assay Kit (Cell Signaling Transduction) according to the manufacturer’s instructions.…”

NF-κB in Cancer Immunity: Friend or Foe?

“…It would now be interesting to decipher which cell types and which NF-κB subunit(s) are required for this control of tumor growth. A recent report suggests that p50/p50 homodimers are able to directly repress Gzmb expression in CD8 + T cells, consequently, Nfkb1 −/− mice exhibit a partial resistance to colon tumorigenesis [ 153 ]. In addition, as described above, NF-κB subunits orient the polarization toward Th cell subsets.…”