Spatially restricted tumour-associated and host-associated immune drivers correlate with the recurrence sites of pancreatic cancer

ObjectiveMost patients with pancreatic ductal adenocarcinoma (PDAC) will experience recurrence after resection. Here, we investigate spatially organised immune determinants of PDAC recurrence.DesignPDACs (n=284; discovery cohort) were classified according to recurrence site as liver (n=93/33%), lung...

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Published in:Gut Vol. 72; no. 8; pp. 1523 - 1533
Main Authors: Karamitopoulou, Eva, Wenning, Anna Silvia, Acharjee, Animesh, Zlobec, Inti, Aeschbacher, Pauline, Perren, Aurel, Gloor, Beat
Format: Journal Article
Language:English
Published: England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.08.2023
BMJ Publishing Group LTD
Subjects:
Actin
Adenocarcinoma
Biology
Biomarkers
cancer immunobiology
Cancer therapies
Carcinoma, Pancreatic Ductal - pathology
CD45 antigen
Chemokines
Chemotherapy
Cloning
Dendritic cells
Fibroblasts
Granzyme B
Histology
Humans
Immune response
Immunofluorescence
Immunogenicity
immunohistopathology
Inflammation
Innate immunity
Leukocytes
Leukocytes (neutrophilic)
Liver
Metastases
Metastasis
Next-generation sequencing
Pancreas
Pancreatic cancer
Pancreatic Neoplasms - pathology
Pathology
Patients
Peritoneum
Phenotypes
Prognosis
Proteomics
Recurrence
Signal transduction
Smooth muscle
Stromal cells
Surgery
Surveillance
Transcriptomics
Tumors
γ-Interferon
immunohistopathology
pancreatic cancer
cancer immunobiology
immune response
ISSN:0017-5749, 1468-3288, 1468-3288
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Summary:ObjectiveMost patients with pancreatic ductal adenocarcinoma (PDAC) will experience recurrence after resection. Here, we investigate spatially organised immune determinants of PDAC recurrence.DesignPDACs (n=284; discovery cohort) were classified according to recurrence site as liver (n=93/33%), lung (n=49/17%), local (n=31/11%), peritoneal (n=38/13%) and no-recurrence (n=73/26%). Spatial compartments were identified by fluorescent imaging as: pancytokeratin (PanCK)+CD45− (tumour cells); CD45+PanCK- (leucocytes) and PanCK-CD45- (stromal cells), followed by transcriptomic (72 genes) and proteomic analysis (51 proteins) for immune pathway targets. Results from next-generation sequencing (n=194) were integrated. Finally, 10 tumours from each group underwent immunophenotypic analysis by multiplex immunofluorescence. A validation cohort (n=109) was examined in parallel.ResultsNo-recurrent PDACs show high immunogenicity, adaptive immune responses and are rich in pro-inflammatory chemokines, granzyme B and alpha-smooth muscle actin+ fibroblasts. PDACs with liver and/or peritoneal recurrences display low immunogenicity, stemness phenotype and innate immune responses, whereas those with peritoneal metastases are additionally rich in FAP+ fibroblasts. PDACs with local and/or lung recurrences display interferon-gamma signalling and mixed adaptive and innate immune responses, but with different leading immune cell population. Tumours with local recurrences overexpress dendritic cell markers whereas those with lung recurrences neutrophilic markers. Except the exclusive presence of RNF43 mutations in the no-recurrence group, no genetic differences were seen. The no-recurrence group exhibited the best, whereas liver and peritoneal recurrences the poorest prognosis.ConclusionsOur findings demonstrate distinct inflammatory/stromal responses in each recurrence group, which might affect dissemination patterns and patient outcomes. These findings may help to inform personalised adjuvant/neoadjuvant and surveillance strategies in PDAC, including immunotherapeutic modalities.
Bibliography:Original research
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ISSN:0017-5749
1468-3288
1468-3288
DOI:10.1136/gutjnl-2022-329371