Powerful in vitro tool: Human immune cell-organoid co-cultures

Researchers developed a co-culture system for assessing complex responses to different immunotherapies

The confocal microscopy image shows a co-culture of pancreatic cancer patient-derived organoids with T-cells (blue). For method development, T-cells from a red fluorescence protein (RFP)-transgenic reporter mouse were used.

© Nathalia Ferreira / Max Planck Institute for Multidisciplinary Sciences

The confocal microscopy image shows a co-culture of pancreatic cancer patient-derived organoids with T-cells (blue). For method development, T-cells from a red fluorescence protein (RFP)-transgenic reporter mouse were used.

© Nathalia Ferreira / Max Planck Institute for Multidisciplinary Sciences

New tool: Researchers have developed a multistep in vitro pipeline based on integrated cancer patient derived organoid immune co-cultures to assess complex responses to different immunotherapies.
Sandwich-based co-culture system: The researchers combined pancreatic cancer patient-derived T-cells and HLA-matched patient-derived organoids (PDOs) to evaluate the efficiency and specificity of nanoparticle-based vaccines, including advanced in vitro platforms such as tumor-on-a-chip models.
Possible advantage for patients: The preclinical in vitro pipeline allows for assessment of personalized treatment regimens tailored to individual cancer patient profiles.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with an overall five-year survival rate of about 13 % and a rising global incidence. To better evaluate complex immunotherapies for the treatment of aggressive PDAC in a human-relevant setting, researchers of the Translational Molecular Imaging group, headed by Frauke Alves at the Max Planck Institute for Multidisciplinary Sciences and the University Medical Center Göttingen, have developed a multi-stage pipeline based on integrated organoid-immune cell co-cultures.

The team co-cultured PDAC patient-derived organoids (PDOs) and matched HLA immune cells to assess the specificity and effectivity of a nanoparticle-based vaccine targeted at mesothelin (MSLN) as monotherapy or in combination with FOLFIRINOX chemotherapy and Atezolizumab immunotherapy.

Evaluating nanovaccine efficiency and specificity

An in-depth quantification of T-cell immune response to the nanovaccine was ensured by starting with the characterization of the T-cell activation in dependence of the vaccine components and continuing with the expansion and profiling of reactive T-cells by employing artificial antigen-presenting cells (aAPCs). This information was used to set up sandwich-based co-cultures of PDAC PDOs and HLA-matched PDAC patient-derived T-cells to evaluate nanovaccine efficiency and specificity, including advanced in vitro models such as tumor-on-a-chip.

Stimulated T-cells, derived from PDAC patients, showed increased interferon-γ production and selective infiltration into MSLN-expressing PDOs. aAPCs boosted the expansion of reactive T-cells, enhancing antitumor responses. Notably, combining the nanovaccine with FOLFIRINOX and Atezolizumab maintained PD-L1+ T-cell levels and reduced cancer stem cells and aggressive PDAC subsets.

Powerful tool

As organoids preserve the genetic features of patient-derived tumor tissue, this comprehensive workflow represents a powerful in vitro tool for assessing complex responses to different immunotherapies, including cancer vaccines. Therefore, it holds significant promise for preclinical testing of personalized treatment regimens tailored to individual cancer patient profiles.

The study was funded by H2020 European Research Council (Grant Number: 861190 (PAVE)), Niedersächsisches Ministerium für Wissenschaft und Kultur (Grant Number: Agile bio-inspired architectures (ABA)), and DFG (Grant Number: 442249343, BD LSRFortessa X-20, Becton Dickinson).