Developing agents to target IL-8 signaling and intercept progression to esophageal adenocarcinoma

The goal of this research was to investigate whether agents targeting Interleukin (IL)-8 and its chemokine receptors (CXCR) 1 and 2 can be identified and exploited to intercept the progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC). Experimental approaches investigated circulating and transcript level changes in IL-8 and CXCR1/2 in EAC progressors and patients with BE, the only known precursor lesion, compared to non-cancer controls or normal tissue, respectively. Gene set enrichment analysis (GSEA) investigated the IL-8 signaling axis in esophageal tissues with progressive pathology changes from BE with low-grade dysplasia (BE.LGD) to BE with high-grade dysplasia (BE.HGD) and EAC. Deconvolution analysis further assessed immune cell alterations in this cohort. Finally, EAC and BE cell lines were employed to investigate various IL-8 assays and determine whether select agents targeting IL-8 signaling induced cell death in BE.HGD or EAC cells. Results showed that plasma IL-8 levels were 3.6-fold (p=0.039) higher in EAC patients compared to non-cancer controls. Moreover, significantly elevated tissue levels of IL-8, CXCR1 and CXCR2 were detected in BE.HGD or EAC compared to BE.LGD. GSEA further implicated the IL-8-CXCR-signaling axis by revealing that 60% of the up-regulated pathway maps during EAC progression contained IL-8 or its receptors (i.e., IL-8-dependent cell migration and adhesion, neutrophil chemotaxis and release of pro-inflammatory factors). Deconvolution analysis identified alterations in multiple immune cell populations with BE progression (BE.LGD to BE.HGD), including up-regulation of neutrophils, which secrete IL-8 and are an abundant cell type at sites of inflammation. Conversely, NK cells, which respond to cellular stress and mediate tumor killing, were downregulated. Proof-of-concept studies conducted in BE.HGD and EAC cell lines showed that a natural product, cranberry proanthocyanidins, as well as the drug lanraplenib, both significantly inhibited IL-8 secretion, followed by potent cell death induction. However, a recent clinical trial with lanraplenib resulted in unacceptable toxic side effects. Ultimately, these results support that IL-8 signaling is induced early during the transition from BE.LGD to BE.HGD and that elevated levels are sustained through EAC development. Thus, we plan to screen the NCI's natural product library for agents that inhibit the IL-8-CXCR-immune signaling axis and that, in turn, may offer efficacious options to intercept BE progression to EAC. This research was supported in part by NCI 1UG3CA299397-01, along with other funding sources.