Bioengineering a Patient-Derived Vascularized Lung Tumor-on-Chip Model to Decipher Immunomodulation by the...

Area of Science:

• Oncology
• Biomedical Engineering
• Cell Biology

Background:

• The tumor microenvironment (TME) is critical for cancer progression.
• Existing tumor-on-chip models often lack clinical relevance and patient-specific components.
• Endothelial cells (ECs) play a vital role in tumor initiation and progression.

Purpose of the Study:

• To develop a clinically relevant 3D vascularized tumor-on-chip (vToC) model using patient-derived cells.
• To investigate the interplay between endothelial cells and other tumor microenvironment components.
• To understand how cancer cells and cancer-associated fibroblasts (CAFs) affect endothelial cell function and immune infiltration.

Main Methods:

• Generation of a 3D vToC model using patient-derived microvascular endothelial cells (ECs) from lung cancer samples.
• Characterization of microvessel identity, morphology, and function via transcriptomics, immunofluorescence, TNF-α stimulation, and permeability assays.
• Embedding lung cancer cells, CAFs, and CD8+ tumor-infiltrating lymphocytes within a collagen matrix to simulate the TME.

Main Results:

• Successfully generated a personalized, immunocompetent vToC model with autologous cell types.
• Transcriptomic analysis revealed decreased expression of VCAM-1 and immunomodulatory chemokines by ECs in the presence of cancer cells and CAFs.
• Demonstrated endothelial cell anergy, recapitulating a key aspect of the tumor microenvironment's impact on immune regulation.

Conclusions:

• The developed vToC model offers a clinically relevant platform for studying the tumor microenvironment.
• This model effectively recapitulates the interplay between endothelial cells, cancer cells, CAFs, and immune cells.
• The findings highlight how cancer cells and CAFs induce endothelial cell anergy, potentially impairing immune surveillance and infiltration.