Affiliation:
1. Division of Gastroenterology and Hepatology, Department of Medicine University of Arizona College of Medicine Tucson AZ USA
2. Department of Optical Sciences University of Arizona Wyant College of Optical Sciences Tucson AZ USA
3. Department of Internal Medicine, Endocrinology University of Michigan Ann Harbor MI USA
Abstract
AbstractGastroenteropancreatic neuroendocrine tumors (GEP‐NETs) are heterogeneous malignancies that arise from complex cellular interactions within the tissue microenvironment. Here, we sought to decipher tumor‐derived signals from the surrounding microenvironment by applying digital spatial profiling (DSP) to hormone‐secreting and non‐functional GEP‐NETs. By combining this approach with in vitro studies of human‐derived organoids, we demonstrated the convergence of cell autonomous immune and pro‐inflammatory proteins that suggests their role in neuroendocrine differentiation and tumorigenesis. DSP was used to evaluate the expression of 40 neural‐ and immune‐related proteins in surgically resected duodenal and pancreatic NETs (n = 20) primarily consisting of gastrinomas (18/20). A total of 279 regions of interest were examined between tumors, adjacent normal and abnormal‐appearing epithelium, and the surrounding stroma. The results were stratified by tissue type and multiple endocrine neoplasia I (MEN1) status, whereas protein expression was validated by immunohistochemistry (IHC). A tumor immune cell autonomous inflammatory signature was further evaluated by IHC and RNAscope, while functional pro‐inflammatory signaling was confirmed using patient‐derived duodenal organoids. Gastrin‐secreting and non‐functional pancreatic NETs showed a higher abundance of immune cell markers and immune infiltrate compared with duodenal gastrinomas. Compared with non‐MEN1 tumors, MEN1 gastrinomas and preneoplastic lesions showed strong immune exclusion and upregulated expression of neuropathological proteins. Despite a paucity of immune cells, duodenal gastrinomas expressed the pro‐inflammatory and pro‐neural factor IL‐17B. Treatment of human duodenal organoids with IL‐17B activated NF‐κB and STAT3 signaling and induced the expression of neuroendocrine markers. In conclusion, multiplexed spatial protein analysis identified tissue‐specific neuro‐immune signatures in GEP‐NETs. Duodenal gastrinomas are characterized by an immunologically cold microenvironment that permits cellular reprogramming and neoplastic transformation of the preneoplastic epithelium. Moreover, duodenal gastrinomas cell autonomously express immune and pro‐inflammatory factors, including tumor‐derived IL‐17B, that stimulate the neuroendocrine phenotype. © 2024 The Pathological Society of Great Britain and Ireland.
Funder
National Institute of Diabetes and Digestive and Kidney Diseases
Subject
Pathology and Forensic Medicine