Hyperactive gp130/STAT3‐driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development

Abstract

Tertiary lymphoid structures (TLSs) display phenotypic and functional characteristics of secondary lymphoid organs, and often develop in tissues affected by chronic inflammation, as well as in certain inflammation‐associated cancers where they are prognostic of improved patient survival. However, the mechanisms that govern the development of tumour‐associated TLSs remain ill‐defined. Here, we observed tumour‐associated TLSs in a preclinical mouse model (gp130 F/F) of gastric cancer, where tumourigenesis is dependent on hyperactive STAT3 signalling through the common IL‐6 family signalling receptor, gp130. Gastric tumourigenesis was associated with the development of B and T cell‐rich submucosal lymphoid aggregates, containing CD21+ cellular networks and high endothelial venules. Temporally, TLS formation coincided with the development of gastric adenomas and induction of homeostatic chemokines including Cxcl13, Ccl19 and Ccl21. Reflecting the requirement of gp130‐driven STAT3 signalling for gastric tumourigenesis, submucosal TLS development was also STAT3‐dependent, but independent of the cytokine IL‐17 which has been linked with lymphoid neogenesis in chronic inflammation and autoimmunity. Interestingly, upregulated lymphoid chemokine expression and TLS formation were also observed in a chronic gastritis model induced by Helicobacter felis infection. Tumour‐associated TLSs were also observed in patients with intestinal‐type gastric cancer, and a gene signature linked with TLS development in gp130 F/F mice was associated with advanced clinical disease, but was not prognostic of patient survival. Collectively, our in vivo data reveal that hyperactive gp130‐STAT3 signalling closely links gastric tumourigenesis with lymphoid neogenesis, and while a TLS gene signature was associated with advanced gastric cancer in patients, it did not indicate a favourable prognosis.

Review: Helicobacter: Inflammation, immunology, and vaccines

“…Hyperactivation of STAT3 signaling promotes both gastric tumorigenesis and lymphoid tissue formation. 14 It is possible that hostderived EVs in H pylori infection represent yet another mechanism by which the bacterium mediates inflammation.…”

PLXNC1 Enhances Carcinogenesis Through Transcriptional Activation of IL6ST in Gastric Cancer

“…These findings showed that IL6ST might be the direct downstream target of PLXNC1. IL6ST (also known as GP130) controls the IL-6/STAT3 signaling pathway and accelerates gastric tumorigenesis (14,15). We performed ChIP-qPCR and found PLXNC1 was enriched on the IL6ST promoter (Figure 5C), further identifying the expressional control of IL6ST by PLXNC1 under a DNA lever.…”

Expression pattern of CDK12 protein in gastric cancer and its positive correlation with CD8+ cell density and CCL12 expression

“…In gastric cancer, high expression of CCL21 in tumor tissues was correlated with tumor invasion and lymph node metastasis [22] . Induction of CCL21 was found in tertiary lymphoid structures which participated in development of inflammation-associated cancer in spontaneous gastric tumorigenesis model [23] . For immune cells, CCL21 can induce several processes of immune response activation including co-localization and recruitment of T cells and dendritic cells; improving cell migration; co-stimulation of naïve T cell expansion and Th1 polarization [21] .…”