Enabling continuous immune cell recirculation on a microfluidic array to study immunotherapeutic interactions in a recapitulated tumour microenvironment

• Published in: Lab on a chip Vol. 24; no. 3; pp. 396 - 47
• Main Authors: Chi, Chun-Wei, Lao, Yeh-Hsing, Ahmed, A. H. Rezwanuddin, He, Siyu, Merghoub, Taha, Leong, Kam W, Wang, Sihong
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 30.01.2024
• Subjects: Antibodies; Arrays; Barriers; Cancer; Cell death; Circulatory system; Endothelium; Fibroblasts; Fluidic circuits; Humans; Immune system; Immunotherapy; Infiltration; Lymphocytes; Microfluidic devices; Microfluidics; Neoplasms; T-Lymphocytes; Tumor Microenvironment; Tumors
• ISSN: 1473-0197; 1473-0189; 1473-0189
• DOI: 10.1039/d3lc00662j

The effects of immunotherapeutics on interactions between immune and cancer cells are modulated by multiple components in the tumour microenvironment (TME), including endothelium and tumour stroma, which provide both a physical barrier and immunosuppressive stimuli. Herein, we report a recirculating chip to enable continuous immune cell recirculation through a microfluidic cell array to include these crucial players. This system consists of a three-layered cell array (μFCA) spatially emulating the TME, with tailored fluidic circuits establishing T cell recirculation. This platform enables the study of dynamics among the TME, immune cells in a circulatory system and cancer cell responses thereof. Through this system, we found that tumour endothelium hindered T cell infiltration into the reconstructed breast cancer tumour compartment. This negative effect was alleviated when treated with anti-human PD-L1 (programmed cell death ligand 1) antibody. Another key stromal component - cancer associated fibroblasts - attenuated T cell infiltration, compared against normal fibroblasts, and led to reduced apoptotic activity in cancer cells. These results confirm the capability of our tumour-on-a-chip system in identifying some key axes to target in overcoming barriers to immunotherapy by recapitulating immune cell interactions with the reconstructed TME. Our results also attest to the feasibility of scaling up this system for high-throughput cancer immunotherapeutic screening. We developed a tumour-on-a-chip system that recapitulated dynamic interplay between immunotherapeutics, regenerated microvessels, tumor stroma and recirculating immune cells.