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Front Immunol. 2018 Mar 6;9:416. doi: 10.3389/fimmu.2018.00416. eCollection 2018.

Characterizing the Role of Monocytes in T Cell Cancer Immunotherapy Using a 3D Microfluidic Model.

Author information

1
BioSystems and Micromechanics IRG, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore.
2
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
3
Singapore Immunology Network (SIgN), Biomedical Sciences Institute, Agency for Science, Technology, and Research, Singapore, Singapore.
4
Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore, Singapore.
5
Programme of Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
6
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States.

Abstract

In the hepatitis B virus (HBV)-related hepatocellular carcinoma tumor microenvironment (TME), monocytes reportedly impede natural T cell functions via PD-L1/PD-1 signaling. However, it remains unclear if T cell receptor-redirected T cells (TCR T cells) are similarly inhibited. Hence, we developed a 3D intrahepatic TME microfluidic model to investigate the immunosuppressive potential of monocytes toward HBV-specific TCR T cells and the role of PD-L1/PD-1 signaling. Interestingly, in our 3D static microfluidic model, we observed that monocytes suppressed only retrovirally transduced (Tdx) TCR T cell cytotoxicity toward cancer cells via PD-L1/PD-1, while mRNA electroporated (EP) TCR T cell cytotoxicity was not affected by the presence of monocytes. Importantly, when co-cultured in 2D, both Tdx and EP TCR T cell cytotoxicity toward cancer cells were not suppressed by monocytes, suggesting our 3D model as a superior tool compared to standard 2D assays for predicting TCR T cell efficacy in a preclinical setting, which can thus be used to improve current immunotherapy strategies.

KEYWORDS:

PD-L1; T cell receptor-redirected T cells; immune checkpoint; immunotherapy; microfluidics; monocytes; tumor microenvironment

PMID:
29559973
PMCID:
PMC5845585
DOI:
10.3389/fimmu.2018.00416
[Indexed for MEDLINE]
Free PMC Article

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