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Advanced Human Immune Cell-Organoid Co-Cultures for Functional Testing of Cancer Nanovaccines
Nathalia Ferreira1, David Agorku2, Andre Rosa3
1Translational Molecular Imaging, Max-Planck-Institute For Multidisciplinary Sciences, Göttingen, Germany.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) remains a major clinical challenge due to late detection and limited treatment responsiveness. To better evaluate complex immunotherapies in a human-relevant setting, we developed an integrated organoid-immune co-culture pipeline using PDAC patient-derived organoids (PDOs) and matched HLA immune cells. As a proof of concept, we assessed an MSLN-targeted nanovaccine (Mesovac), alone and in combination with FOLFIRINOX chemotherapy and Atezolizumab. We evaluated Mesovac across a multi-stage pipeline, including T-cell stimulation, ex vivo expansion, and PDO-immune co-cultures, to assess immune activation, specificity, and synergy with combinatorial treatments. MSLN-stimulated T-cells, derived from PDAC patients, showed increased IFN-γ production and selective infiltration into MSLN-expressing PDOs. Artificial antigen-presenting cells (aAPCs) boosted the expansion of reactive T-cells, enhancing antitumor responses. Notably, combining Mesovac with FOLFIRINOX and Atezolizumab maintained PD-L1+ T-cell levels and reduced cancer stem cells and aggressive PDAC subsets. Using this advanced in vitro workflow, we highlight that this platform, using human organoid-immune cell co-cultures, enables the evaluation of complex processes related to nanovaccine strategies that would not be possible in vivo.
Insights
This study introduces a novel organoid-immune co-culture pipeline for evaluating pancreatic cancer immunotherapies. The platform successfully assessed a nanovaccine, demonstrating its potential in combination treatments.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents significant clinical challenges due to late diagnosis and poor treatment outcomes.
- Evaluating complex immunotherapies requires human-relevant models that recapitulate tumor microenvironment interactions.
Purpose of the Study:
- To develop and validate an integrated organoid-immune co-culture pipeline for assessing novel immunotherapies in PDAC.
- To evaluate the efficacy of an MSLN-targeted nanovaccine (Mesovac) in combination with standard treatments.
Main Methods:
- Utilized patient-derived organoids (PDOs) and matched HLA-matched immune cells for co-culture systems.
- Assessed Mesovac efficacy through T-cell stimulation, ex vivo expansion, and PDO-immune co-cultures.
- Incorporated artificial antigen-presenting cells (aAPCs) to enhance T-cell responses.
Main Results:
- MSLN-stimulated T-cells from PDAC patients demonstrated increased IFN-γ production and selective infiltration into MSLN-expressing PDOs.
- aAPCs significantly boosted the expansion of tumor-reactive T-cells, improving antitumor activity.
- Combination therapy (Mesovac, FOLFIRINOX, Atezolizumab) maintained PD-L1+ T-cells and reduced cancer stem cells and aggressive PDAC subtypes.
Conclusions:
- The developed organoid-immune co-culture platform provides a robust in vitro model for evaluating complex nanovaccine strategies in PDAC.
- This human-relevant system facilitates the assessment of immune activation, specificity, and synergistic effects of combinatorial therapies.
