Tumour-infiltrating adipocyte-derived 12,13-DiHOME subverts CD8+ T cell immunity in pancreatic ductal adenocarcinoma by promoting PPAR
Menée notamment à l'aide de modèles murins d'adénocarcinome canalaire du pancréas et de données portant sur 121 patients puis validée à partir de données transcriptomiques, cette étude met en évidence un mécanisme par lequel le lipide 12,13-DiHOME, sécrété par les adipocytes ayant infiltré la tumeur, réduit les capacités immunitaires des lymphocytes T CD8+ en favorisant la ferritinophagie induite par le récepteur PPARgamma et la ferroptose des neutrophiles associés à la tumeur
Background : Pancreatic ductal adenocarcinoma (PDAC) frequently invades adjacent peripancreatic adipose tissue, yet the role of tumour-infiltrating adipocytes (TIAs) in shaping antitumour immunity remains unclear.
Objective : To determine how TIAs influence PDAC progression and to define the immunometabolic mechanism involved.
Design : We used orthotopic PDAC models and Kras(LSL-G12D/+);Trp53(LSL-R172H/+);Pdx1-Cre (KPC) mice, together with neutrophil lineage peroxisome proliferator-activated receptor gamma (PPAR
γ) conditional knockout mice (PPARγ(fl/fl)-S100A8(cre)). Tumour metabolomics, bulk RNA sequencing (bulk RNA-seq) and single-cell RNA sequencing (scRNA-seq) were integrated with adipocyte and tumour-associated neutrophil (TAN) co-culture assays. Human relevance was assessed in a retrospective PDAC cohort (n=121) and validated in public transcriptomic datasets.
Results
:
High TIA abundance correlated with poorer overall survival and an immune-suppressed tumour microenvironment (TME). In mouse models, adipocyte-enriched tumours showed reduced CD8+ T cell functions. Multiomics analyses highlighted the adipocyte-derived metabolite 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME) and supported its role in increasing TAN ferroptosis susceptibility. Mechanistically, 12,13-DiHOME enhanced PPARγ-dependent ferritinophagy signalling in TANs, accompanied by increased ferroptosis and CXCL2 production. Genetic or pharmacologic disruption of this axis, CXCL2 neutralisation or CXCR2 blocking, attenuated tumour-promoting phenotypes and restored CD8+ T cell functions in vivo and in vitro.
Conclusions
:
These findings support an adipocyte-TAN immunometabolic circuit in PDAC, where TIA-derived 12,13-DiHOME promotes PPARγ-dependent TAN ferroptosis and increases CXCL2, leading to impaired CD8+ T
cell functions. Targeting this pathway may help mitigate immune suppression in PDAC.
Gut , article en libre accès, 2026