RT Journal Article SR Electronic T1 Immune landscape, evolution, hypoxia-mediated viral mimicry pathways and therapeutic potential in molecular subtypes of pancreatic neuroendocrine tumours JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP 1904 OP 1913 DO 10.1136/gutjnl-2020-321016 VO 70 IS 10 A1 Young, Kate A1 Lawlor, Rita T A1 Ragulan, Chanthirika A1 Patil, Yatish A1 Mafficini, Andrea A1 Bersani, Samantha A1 Antonello, Davide A1 Mansfield, David A1 Cingarlini, Sara A1 Landoni, Luca A1 Pea, Antonio A1 Luchini, Claudio A1 Piredda, Liliana A1 Kannan, Nagarajan A1 Nyamundanda, Gift A1 Morganstein, Daniel A1 Chau, Ian A1 Wiedenmann, Bertram A1 Milella, Michele A1 Melcher, Alan A1 Cunningham, David A1 Starling, Naureen A1 Scarpa, Aldo A1 Sadanandam, Anguraj YR 2021 UL http://gut.bmj.com/content/70/10/1904.abstract AB Objective A comprehensive analysis of the immune landscape of pancreatic neuroendocrine tumours (PanNETs) was performed according to clinicopathological parameters and previously defined molecular subtypes to identify potential therapeutic vulnerabilities in this disease.Design Differential expression analysis of 600 immune-related genes was performed on 207 PanNET samples, comprising a training cohort (n=72) and two validation cohorts (n=135) from multiple transcriptome profiling platforms. Different immune-related and subtype-related phenotypes, cell types and pathways were investigated using different in silico methods and were further validated using spatial multiplex immunofluorescence.Results The study identified an immune signature of 132 genes segregating PanNETs (n=207) according to four previously defined molecular subtypes: metastasis-like primary (MLP)-1 and MLP-2, insulinoma-like and intermediate. The MLP-1 subtype (26%–31% samples across three cohorts) was strongly associated with elevated levels of immune-related genes, poor prognosis and a cascade of tumour evolutionary events: larger hypoxic and necroptotic tumours leading to increased damage-associated molecular patterns (viral mimicry), stimulator of interferon gene pathway, T cell-inflamed genes, immune checkpoint targets, and T cell-mediated and M1 macrophage-mediated immune escape mechanisms. Multiplex spatial profiling validated significantly increased macrophages in the MLP-1 subtype.Conclusion This study provides novel data on the immune microenvironment of PanNETs and identifies MLP-1 subtype as an immune-high phenotype featuring a broad and robust activation of immune-related genes. This study, with further refinement, paves the way for future precision immunotherapy studies in PanNETs to potentially select a subset of MLP-1 patients who may be more likely to respond.All data relevant to the study are included in the article or uploaded as supplementary information. Data are available in GEO Omnibus (GEO Omnibus with IDs GSE73338 and GSE73339): (1) the data include transcriptome profiles from patient samples; (2) GEO Omnibus is the repository; and (3) there are no reuse conditions. We have included the information and GEO Omnibus IDs in the Materials and methods and supplemental information.