Extracellular Vesicle Mediated Tumor-Stromal Crosstalk Within an Engineered Lung Cancer Model

Tumor-stromal interactions within the tumor microenvironment (TME) influence lung cancer progression and response to therapeutic interventions, yet traditional in vitro studies fail to replicate the complexity of these interactions. Herein, we developed three-dimensional (3D) lung tumor models that mimic the human TME and demonstrate tumor-stromal crosstalk mediated by extracellular vesicles (EVs). EVs released by tumor cells, independent of p53 status, and fibroblasts within the TME mediate immunomodulatory effects; specifically, monocyte/macrophage polarization to a tumor-promoting M2 phenotype within this 3D-TME. Additionally, immune checkpoint inhibition in a 3D model that included T cells showed an inhibition of tumor growth and reduced hypoxia within the TME. Thus, perfused 3D tumor models incorporating diverse cell types provide novel insights into EV-mediated tumor-immune interactions and immune-modulation for existing and emerging cancer therapies.

Automated summary

This study developed three-dimensional lung tumor models to mimic the human tumor microenvironment, demonstrating interactions between tumors and stroma mediated by extracellular vesicles (EVs) and their influence on immunomodulation. Inhibiting immune checkpoints in a 3D model including T cells showed suppression of tumor growth and reduction of hypoxia within the tumor microenvironment.