PT  - JOURNAL ARTICLE
AU  - Kate Young
AU  - Rita T Lawlor
AU  - Chanthirika Ragulan
AU  - Yatish Patil
AU  - Andrea Mafficini
AU  - Samantha Bersani
AU  - Davide Antonello
AU  - David Mansfield
AU  - Sara Cingarlini
AU  - Luca Landoni
AU  - Antonio Pea
AU  - Claudio Luchini
AU  - Liliana Piredda
AU  - Nagarajan Kannan
AU  - Gift Nyamundanda
AU  - Daniel Morganstein
AU  - Ian Chau
AU  - Bertram Wiedenmann
AU  - Michele Milella
AU  - Alan Melcher
AU  - David Cunningham
AU  - Naureen Starling
AU  - Aldo Scarpa
AU  - Anguraj Sadanandam
TI  - Immune landscape, evolution, hypoxia-mediated viral mimicry pathways and therapeutic potential in molecular subtypes of pancreatic neuroendocrine tumours
AID  - 10.1136/gutjnl-2020-321016
DP  - 2021 Oct 01
TA  - Gut
PG  - 1904--1913
VI  - 70
IP  - 10
4099  - http://gut.bmj.com/content/70/10/1904.short
4100  - http://gut.bmj.com/content/70/10/1904.full
SO  - Gut2021 Oct 01; 70
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.