Loss of NF-κB1 Promotes Inflammation and Immune Checkpoint Regulators

NFKB1 polymorphisms that result in decreased NF-KB1 expression have been associated with both inflammatory diseases and epithelial cancers, but the role of NF-KB1 deficiency in these diseases has not been described. To elucidate the mechanism by which NF-κB1 loss promotes gastric cancer, O'Reilly, Putoczki, and colleagues performed gastric histopathologic characterization of Nfkb1^−/− mice, which have previously been shown to develop systemic inflammation. Compared to wild-type mice, Nfkb1^−/− mice initially exhibited inflammatory cell infiltration and diffuse gastritis, and subsequently developed gastric adenocarcinomas. Further, bone marrow reconstitution experiments revealed that both NF-κB1–deficient epithelial and hematopoietic cells were critical for gastric cancer development, and gastric cancer development in Nfkb1^−/− mice was unaffected by the presence of microorganisms associated with gastric inflammation, such as Heliobacter pylori. Analysis of the composition of NF-κB complexes identified NF-κB1 as the predominant nuclear NF-κB complex in wild-type mice, and dysplastic gastric glands exhibited punctate nuclear pRELA positivity in Nfkb1^−/− mice with established disease whereas predominantly cytoplasmic pRELA was observed in the gastric glands of precancerous mice. Loss of Nfkb1 resulted in the increased expression of genes encoding known NF-κB targets, cytokines, and chemokines in epithelial, myeloid, and lymphoid cells. Bioinformatic and flow cytometric analyses revealed that Nfkb1 deficiency promoted the upregulation of antigen processing and presentation and JAK/STAT signaling in gastric cancer, and immune checkpoint signaling in myeloid cells during early gastric cancer development and in epithelial cells in established disease. Moreover, Nfkb1 deficiency promoted gastritis and gastric cancer development in a STAT1-dependent manner, and loss of both Stat1 alleles, but not a single Stat1 allele, inhibited gastric cancer development and PD-L1 myeloid expression in Nfkb1^−/− mice. Taken together, these findings identify the tumor-suppressive role of NF-κB1 in gastric cancer and provide a rationale for clinically developing the combination of clinical JAK/STAT inhibitors and immune checkpoint therapies for patients with gastric cancer.

O'Reilly LA, Putoczki TL, Mielke LA, Low JT, Lin A, Preaudet A, et al. Loss of NF-κB1 causes gastric cancer with aberrant inflammation and expression of immune checkpoint regulators in a STAT-1-dependent manner. Immunity 2018;48:570–83.

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