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bioRxiv · 10.1101/2023.07.01.547336

Spatial profiling of neuro-immune interactions in gastroenteropancreatic NETs

Duan, S.·Sawyer, T. W.·Witten, B. L.·Song, H.·Else, T.·Merchant, J. L.
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Abstract

Gastroenteropancreatic 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 Nanostring Digital Spatial Profiling (DSP) to hormone-secreting and non-functional GEP-NETs. DSP was used to evaluate the expression of 40 neural and immune-related proteins in surgically resected duodenal and pancreatic NETs (n=20) primarily comprised 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 and protein expression was validated by immunohistochemical (IHC) staining. 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 to duodenal gastrinomas. Tumors displayed strong intra-tissue variation in the expression of neural- and immune-related proteins. Compared to non-MEN1 tumors, MEN1 gastrinomas showed reduced expression of immune cell markers and upregulated expression of neuropathological proteins. Duodenal gastrinomas showed strong expression of the pro- inflammatory and pro-neural factor IL-17B. Treatment of human duodenal organoids with IL- 17B activated NF-kB 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. Moreover, duodenal gastrinomas cell autonomously express immune and pro-inflammatory factors, including tumor-derived IL-17B, that stimulate the neuroendocrine phenotype.

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Duan, S., Sawyer, T. W., Witten, B. L., Song, H., Else, T., Merchant, J. L.. 2023-07-02. Spatial profiling of neuro-immune interactions in gastroenteropancreatic NETs. https://doi.org/10.1101/2023.07.01.547336

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