Advanced Human Immune Cell-Organoid Co-Cultures for Functional Testing of Cancer Nanovaccines

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.