Intertumoral lineage diversity and immunosuppressive transcriptional programs in well-differentiated gastroenteropancreatic neuroendocrine tumors

Neuroendocrine tumors (NETs) are rare cancers that may arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic (GEP) NET growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we investigated the single-cell transcriptomes of tumor and immune cells from patients with gastroenteropancreatic NETs. Malignant GEP-NET cells expressed genes and regulons associated with normal, gastrointestinal endocrine cell differentiation and fate determination stages. While tumor and lymphoid compartments sparsely expressed immunosuppressive targets, infiltrating myeloid cells were enriched for alternative immunotherapy pathways including VSIR, Tim3/Gal9, and SIGLEC10. Finally, analysis of paired primary and metastatic tissue specimens from small intestinal NETs demonstrated transcriptional transformation between the primary tumor and its distant metastasis. Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics. ### Competing Interest Statement AR is an equity holder in Celsius Therapeutics and NucleAI. J.C. reports consulting relationships with Advanced Accelerator Applications and TerSera and equity in Merck. E.M.V.A reports advisory and consulting relationships with Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Janssen, Manifold Bio, and Monte Rosa; research support from Novartis and BMS; equity in Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, and Monte Rosa; institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation; intermittent legal consulting on patents for Foaley & Hoag; and serves on the Editorial Boards of JCO Precision Oncology and Science Advances. All other authors declare they have no competing interests.