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Front. Immunol. | doi: 10.3389/fimmu.2018.00416

Characterizing the role of monocytes in T cell cancer immunotherapy using a 3D microfluidic model.

  • 1Singapore Immunology Network (A*STAR), Singapore
  • 2BioSystems and Micromechanics IRG, Singapore-MIT Alliance for Research and Technology, Singapore
  • 3Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  • 4Institute of Molecular and Cell Biology (A*STAR), Singapore
  • 5Duke Medical School, National University of Singapore, Singapore
  • 6Department of Biological Engineering, Massachusetts Institute of Technology, United States

In the hepatitis-B virus-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 (TCR)-redirected T cells are similarly inhibited. We thus 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 pre-clinical setting, that can thus be used to improve current immunotherapy strategies.

Keywords: Microfluidics, Monocytes, T cell receptor-redirected T cells, Immunotherapy, Immune checkpoint, PD-L1, Tumor Microenvironment

Received: 13 Sep 2017; Accepted: 15 Feb 2018.

Edited by:

Vincenzo Bronte, University of Verona, Italy

Reviewed by:

Tanja D. De Gruijl, VU University Medical Center, Netherlands
Thorbald Van Hall, Leiden University, Netherlands  

Copyright: © 2018 Lee, Adriani, Ceccarello, Pavesi, Tan, Bertoletti, Kamm and Wong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Roger D. Kamm, Singapore-MIT Alliance for Research and Technology, BioSystems and Micromechanics IRG, 1 Create Way, #04-13/14 Enterprise Wing, Singapore, 138602, Singapore, rdkamm@MIT.EDU
Dr. Siew Cheng Wong, Singapore Immunology Network (A*STAR), 8A Biomedical Grove, Immunos level 4, Biopolis, Singapore, 138648, Singapore, wong_siew_cheng@immunol.a-star.edu.sg