AI Insight
This study investigated how increasing body weight affects the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) using transcriptomic data from 140 patients. Using Bayesian hierarchical modeling and cell-type deconvolution, the researchers found that the overweight state, rather than clinical obesity, represents an early tipping point at which significant immune and stromal reprogramming occurs, including a shift from adaptive T cell and dendritic cell-driven immune interactions toward a neutrophil-dominated inflammatory network. Cell-type-specific analysis revealed non-linear dynamics, including CD4+ T cell functional collapse in obesity, progressive CD8+ T cell exhaustion, and spatial compression of CD8+ T cells toward the tumor boundary with increasing BMI.
Why it matters
These findings suggest that metabolic interventions targeting the overweight stage, before clinical obesity is established, may represent a critical window to prevent immune deterioration in PDAC patients and potentially improve treatment outcomes in one of the deadliest cancers.
⚠️ Preprint – Noch nicht peer-reviewed
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Background: Obesity significantly increases the risk of prognosis and clinical outcomes in pancreatic ductal adenocarcinoma (PDAC). While research on the interactions between obesity and the tumor microenvironment (TME) is mostly confined to a few interactions at a time, leaving a gap in the comprehensive understanding of obesity-driven PDAC. We set out to develop a cell-type-resolved model of obesity-driven PDAC using bulk transcriptomic data to investigate TME changes. Methods: We conducted an integrated transcriptomic analysis of PDAC patients from the CPTAC-3 cohort (n=140) stratified by BMI. A custom immune and stromal functional gene signature database covering 65 cell types was constructed, followed by LLM-assisted review, overlap control, and validation. BayesPrism deconvolution using matched single-cell references was used to derive expression profiles for each cell type. Stabl, a machine-learning algorithm, was used to identify BMI-associated signatures. Bayesian hierarchical modeling, using both continuous and categorical BMI change, was applied to estimate effect sizes and assess the statistical credibility of the signature changes using the 95% Highest Density Interval (HDI) excluding zero. Virtual multiplex immunofluorescence was generated from whole-slide H&E images using gigaTIME to assess the spatial manifestation of BMI-associated TME changes in tissue Results: Bulk pathway analysis showed that ECM homeostasis and primary immunodeficiency pathways deteriorated with increasing BMI. However, Bayesian modeling revealed cell-type-specific, non-linear dynamics. Stromal populations in overweight (OW) individuals were altered, with changes in ECM synthesis and inflammatory signaling that stabilized rather than intensified during obesity. Immune compartments also showed diverse trajectories: CD4+ T cells remained functional in OW but collapsed in obesity; CD8+ T cells progressed linearly from activation to chronic exhaustion. NK cells exhibited non-monotonic behavior, and monocyte and B cell lineages became impaired prior to clinical obesity. Cell-cell interaction analysis showed a shift from a T cell and dendritic cell-centric adaptive interactome in normal weight patients to a neutrophil-dominated inflammatory network in OW. Spatial analysis showed stromal-trapped CD8+ T cells were compressed closer to the tumor boundary with rising BMI. Conclusions: Overweight status represents a critical tipping point in tumor microenvironmental reprogramming, challenging linear models of obesity-associated immune modulation and suggesting that early metabolic interventions may prevent PDAC functional deterioration.