Poster Presentation 37th Lorne Cancer Conference 2025

Modelling T cell and cancer cell interactions to examine immune checkpoint inhibition resistance in pancreatic ductal adenocarcinoma (#155)

Aji Istadi 1 2 , Inna Navarro 1 2 , Sean Porazinski 3 , Marco Herold 4 , Greg Neely 5 , Marina Pajic 1 2
  1. St Vincent's Clinical School, University of New South Wales Sydney, Randwick, NSW, Australia
  2. The Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  3. Inventia Life Science, Alexandria, NSW, Australia
  4. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
  5. Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer, with ~90% of patients dying within 5 years1,2. This dire statistic underscores the limitations of current standard-of-care chemotherapies and the need for improved therapeutic approaches. Immune checkpoint inhibitor (ICI) therapy, which reinvigorates the hosts’ endogenous anti-cancer immune response to eliminate malignant cells, has shown great promise in eliciting long-lived responses across numerous cancer types. However, PDAC is almost completely refractory to ICI therapy, highlighting the incomplete understanding of immune-cancer interactions in this disease.

The “immune-cold” tumour microenvironment is a major contributor to ICI resistance in PDAC, where immunosuppressive immune cells and cancer-associated fibroblasts concertedly antagonise T cell activity3. Additionally, the dense desmoplastic stroma also presents as a physical barrier that restricts T cell infiltration and motility within the tumour4. Developing strategies to overcome these barriers have been challenging, partly due to the difficulty in replicating the complex tumour microenvironment in experimental models, limiting the development of immune modulators to enhance ICI responses.

The use of 3D cancer tumoroid cultures enables more accurate modelling of gene expression patterns and spatial arrangements of cancer cells in tumour environments, allowing for more thorough examination of cell-to-cell and cell-to-environment interactions5. However, most tumoroid cultures rely on the use of commercial matrix products like Matrigel, which has distinct biochemical and mechanical properties compared to native tumours. In this study, we utilise the Inventia RASTRUM drop-on-demand bioprinter to create 3D T cell–cancer cell co-cultures using a tuneable synthetic PEG-based hydrogel matrix, which closely mimics the extracellular environment of PDAC in composition and stiffness6. By characterizing T cell–cancer cell interactions with real-time longitudinal imaging, we demonstrate the advantages of this platform over Matrigel-based models for immuno-oncology applications. Overall, our approach provides a scalable framework for evaluating the potency of immunomodulators for the rational design of ICI combination therapies.