The Impact of Collagen Heterogeneity on the Immune Landscape of Pancreatic Ductal Adenocarcinoma and Its Role in Personalising IL-12- Based Immunotherapy
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Embargo End Date
2025-09-11
ICR Authors
Authors
Ragulan, C
Document Type
Thesis or Dissertation
Date
2025-03-11
Date Accepted
Abstract
The aggressive cancer, pancreatic ductal adenocarcinoma (PDAC), is characterised by an immunosuppressive tumour microenvironment (TME) and collagen-rich desmoplastic stroma. This TME leads to tumour heterogeneity and resistance to therapies, including immunotherapy and patients often rely on toxic chemotherapy. Moreover, second-generation cytokine-based immunotherapy has limited clinical success in pan-cancers. Therefore, I hypothesised that classifying PDACs into immunologically relevant subgroups will improve our understanding of immune heterogeneity and enhance the personalisation of second-generation cytokine-based immunotherapy. To test this hypothesis, a novel 27-exclusive immune gene signature (PDACi) was developed using a unique virtual microdissection analysis of Nanostring gene expression from 22 matched PDAC and patient-derived xenograft (PDX) tumours. The PDACi signature classified PDACs (n=664) into four subtypes: two (immune-depleted/dormant and collagen-enriched) associated with worse survival and two with better prognoses and higher immune cell infiltration. Using cross-species analysis, I identified subtype-specific mouse models (n=12) and tested different immunotherapy modalities, including collagen-bound pro-inflammatory cytokine (CBD-IL-12) therapy, CBD-IL-12 to reduce systemic toxicity compared to wildtype-IL-12. This bioengineered-CBD-IL-12 combined with anti-PD-1 significantly extended survival in mice (p=0.002) with collagen-rich subtype tumours while reducing liver metastasis and cachexia-like features. Spatial and gene expression (Phenocycler, flowcytometry and bulk-deconvolution) analysis showed that CBD-IL-12 treatment increased unusually Th1-polarised cytotoxic CD4+ T-cells and immune-active myeloid cells and reduced Th17-cells and immunosuppressive myeloid cells compared to the control treatment. Mechanistically, CBD-IL-12 combined with anti-PD-1 treatment remodelled the collagen composition in the TME and induced cancer cell dormancy by enhancing the epithelial-like phenotype via IL-7 signalling, thereby reducing metastasis. Intriguingly, CBD-IL-12 treatment had a preventative effect in a liver metastases model. Overall, the immune signature PDACi captures immune heterogeneity, enabling tailored immunotherapy for PDAC subtypes in mouse models, particularly with CBD-IL-12 and PD-1 treatment, with a potential to advance personalised PDAC treatment in patients with further validation.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Systems - Precision Med