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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.
Highlights
Adoptive cell therapy (ACT) consists of the administration of lymphocytes to cancer patients to mediate an anticancer effector response
The PD-L1/PD-1 axis is an important immune checkpoint in hepatitis B virus (HBV)-HCC [18,19,20, 55,56,57]. To determine if this axis is playing a role in our model, we first co-cultured Tdx and EP TCR the HBs183-91-specific (Ts) cells, HepG2-preS1-GFP and monocytes in 2D wells for 24 h as described in Section “Materials and Methods” and measured the surface expression of PD-L1 and PD-1 on the various cell types by flow cytometry
When monocytes were present (Hep Ts monocytes cultured either alone (Mo)), Tdx Ts killing activity was significantly inhibited (Figures 5D,E). These results demonstrate that the 3D microfluidic model is a functional platform that can be used to screen and compare across different co-culture conditions to elucidate the role of monocytes in TCR T cell immunotherapy, whereas standard 2D cytotoxicity assays had failed to do so in this case
Summary
Adoptive cell therapy (ACT) consists of the administration of lymphocytes to cancer patients to mediate an anticancer effector response. The adoptive transfer of the HBV-specific TCR T cells resulted in Abbreviations: TCR T cell, T cell receptor-redirected T cell; EP, electroporated; Tdx, transduced; TME, tumor microenvironment. Strategies utilizing antibodies targeting the PD-L1/PD-1 axis have been approved for use in patients after encouraging clinical trials [24,25,26,27]. Such findings are based on physiological tumor-infiltrating leukocytes (TILs), while the contribution of PD-L1-based signaling on TCR T cell functions remains to be investigated
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