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Updated: Oct 15, 2025
Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
Published on: December 7, 2019
A 3D pancreatic tumor model to study T cell infiltration
Hilaria Mollica1, Yi Juan Teo2, Alrina Shin Min Tan2
1Laboratory of Nanotechnology for Precision Medicine, Italian Institute of Technology, Via Morego 30, Genova, 16163, Italy.
Abstract:
The desmoplastic nature of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) prevents the infiltration of T cells and the penetration of chemotherapeutic drugs, posing a challenge to the validation of targeted therapies, including T cell immunotherapies. We present an in vitro 3D PDAC-TME model to observe and quantify T cell infiltration across the vasculature. In a three-channel microfluidic device, PDAC cells are cultured in a collagen matrix in the central channel surrounded, on one side, by endothelial cells (ECs) to mimic a blood vessel and, on the opposite side, by pancreatic stellate cells (PSCs) to simulate exocrine pancreas. The migration of T cells toward the tumor is quantified based on their activation state and TME composition. The presence of EC-lining drastically reduces T cell infiltration, confirming the essential role of the vasculature in controlling T cell trafficking. We show that activated T cells migrate ∼50% more than the not-activated ones toward the cancer cells. Correspondingly, in the absence of cancer cells, both activated and not-activated T cells present similar migration toward the PSCs. The proposed approach could help researchers in testing and optimizing immunotherapies for pancreatic cancer.
Insights
A novel 3D model simulates the pancreatic cancer microenvironment (TME) to study T cell infiltration. This model reveals that blood vessels significantly hinder T cell entry, impacting immunotherapy effectiveness.
Area of Science:
- Oncology
- Immunology
- Biomedical Engineering
Background:
- Pancreatic ductal adenocarcinoma (PDAC) features a desmoplastic tumor microenvironment (TME) that impedes T cell infiltration and drug delivery.
- This TME presents a significant challenge for developing effective T cell immunotherapies and targeted treatments for pancreatic cancer.
Purpose of the Study:
- To develop and validate an in vitro 3D model of the pancreatic ductal adenocarcinoma tumor microenvironment (PDAC-TME).
- To quantify T cell infiltration across vasculature and assess the impact of TME components on T cell migration.
Main Methods:
- A three-channel microfluidic device was utilized to co-culture pancreatic ductal adenocarcinoma (PDAC) cells within a collagen matrix.
- Endothelial cells (ECs) were cultured on one side to mimic vasculature, and pancreatic stellate cells (PSCs) on the opposite side to simulate the exocrine pancreas.
- T cell migration was quantified based on activation state and TME composition, with a focus on infiltration across the EC layer.
Main Results:
- The presence of an endothelial cell (EC)-lined channel significantly reduced T cell infiltration, highlighting the critical role of vasculature in controlling T cell trafficking.
- Activated T cells demonstrated approximately 50% greater migration towards cancer cells compared to non-activated T cells.
- In the absence of cancer cells, both activated and non-activated T cells showed similar migration patterns towards pancreatic stellate cells (PSCs).
Conclusions:
- The developed 3D PDAC-TME model effectively simulates key aspects of the tumor microenvironment relevant to T cell infiltration.
- The findings underscore the barrier function of tumor vasculature in pancreatic cancer and its implications for T cell-based immunotherapies.
- This model offers a valuable platform for testing and optimizing immunotherapeutic strategies for pancreatic cancer.
