دورية أكاديمية
Immune landscape, evolution, hypoxia-mediated viral mimicry pathways and therapeutic potential in molecular subtypes of pancreatic neuroendocrine tumours.
| العنوان: | Immune landscape, evolution, hypoxia-mediated viral mimicry pathways and therapeutic potential in molecular subtypes of pancreatic neuroendocrine tumours. |
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| المؤلفون: | Young, K, Lawlor, RT, Ragulan, C, Patil, Y, Mafficini, A, Bersani, S, Antonello, D, Mansfield, D, Cingarlini, S, Landoni, L, Pea, A, Luchini, C, Piredda, L, Kannan, N, Nyamundanda, G, Morganstein, D, Chau, I, Wiedenmann, B, Milella, M, Melcher, A, Cunningham, D, Starling, N, Scarpa, A, Sadanandam, A |
| المساهمون: | Ragulan, Chanthirika, Mansfield, David, Melcher, Alan |
| بيانات النشر: | BMJ PUBLISHING GROUP |
| سنة النشر: | 2020 |
| المجموعة: | The Institute of Cancer Research (ICR): Publications Repository |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | Print-Electronic; application/pdf |
| اللغة: | English |
| تدمد: | 0017-5749 1468-3288 |
| العلاقة: | Gut, 2020; https://repository.icr.ac.uk/handle/internal/4063Test |
| DOI: | 10.1136/gutjnl-2020-321016 |
| الإتاحة: | https://doi.org/10.1136/gutjnl-2020-321016Test https://repository.icr.ac.uk/handle/internal/4063Test |
| حقوق: | https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.4CC95F66 |
| قاعدة البيانات: | BASE |
| تدمد: | 00175749 14683288 |
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| DOI: | 10.1136/gutjnl-2020-321016 |