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.
Highlights
Gastric cancer (GC) is the third most lethal cancer worldwide and affects over half a million people per year.[1]
Gastric tumourigenesis in gp130F/F mice is associated with submucosal Tertiary lymphoid structures (TLSs) development The spontaneous development of gastric antrum adenomas in gp130F/F mice is associated with inflammatory infiltrates and accumulations of large extra-tumoural inflammatory aggregates in the gastric submucosa, the latter of which are absent in age-matched 6-month-old control WT mice[24,25,26] (Figs. 1a and 1b)
Consistent with the cellular features of tumour-associated TLSs, immunohistochemistry revealed a typical pattern of lymphoid organisation, with a co-localisation of B2201 B cells and CD31 T cells within cellular aggregates (Fig. 1c)
Summary
Gastric cancer (GC) is the third most lethal cancer worldwide and affects over half a million people per year.[1]. Cancer: 143, 167–178 (2018) VC 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC gp130/STAT3 regulates TLSs in gastric cancer. Tertiary lymphoid structures (TLSs) develop in chronically inflamed tissues, and have been associated with improved survival in certain cancer patients. The authors examined mechanisms governing the development of submucosal TLSs in the gp130F/F mouse model of gastric cancer and in patients afflicted with intestinal-type disease. TLS formation was observed both mice and patients but a TLS gene signature identified in mice did not predict improved patient survival, pointing to need for more research into TLSs and gastric cancer prognosis
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