Abstract
Chronic infection with viral hepatitis is a major risk factor for liver injury and hepatocellular carcinoma (HCC). One major contributing factor to the chronicity is the dysfunction of virus-specific T cell immunity. T cells engineered to express virus-specific T cell receptors (TCRs) may be a therapeutic option to improve host antiviral responses and have demonstrated clinical success against virus-associated tumours. This review aims to give an overview of TCRs identified from viral hepatitis research and discuss how translational lessons learned from cancer immunotherapy can be applied to the field. TCR isolation pipelines, liver homing signals, cell type options, as well as safety considerations will be discussed herein.
Highlights
Cell exhaustion due to the upregulation of inhibitory co-receptors, inefficient priming by CD4+ T cells, suppressive signaling from regulatory Tregs, or the local cytokine milieu can all contribute to cytotoxic T lymphocytes (CTLs)
Cross-reactive T cell receptors (TCRs) in therapy could trigger undesirable off-target toxicity, such as those observed in a melanoma-associated antigen (MAGE)-specific TCR immunotherapy, as these epitopes are originally derived from self-peptides and could still be expressed by normal cells, in this case those found in the cardiac tissue [67]
As the field of TCR-redirected T cell therapy as a cancer treatment rapidly evolves, its application to chronic infection management is likely to be feasible in the near future
Summary
The liver is a critical organ that performs an array of functions to support the bodys metabolism, immunity, digestion, detoxification, and vitamin storage. The tolerogenic environment is evident in its low occurrence of post-transplant rejection, even when accepting a major histocompatibility complex (MHC) mismatched allograft [1] While these immunosuppressive properties may prevent severe autoimmune responses and liver transplant rejections, they are disadvantageous against pathogens that have specialized in infecting the liver. In cases of advanced liver disease, especially in HCC patients, dysfunctional T cell phenotypes are well described, and immune checkpoint molecules such as cytotoxic T-lymphocyte-associated. PD-1 is another checkpoint molecule mainly found on mature peripheral T cells, natural killer (NK) cells, and several APCs. Its ligand, PD-L1, is highly expressed in HCC, and the constitutive activation of this axis leads to T cell exhaustion. Other inhibitory immune checkpoint molecules found to be upregulated in HCC include T cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte-activation gene 3 (LAG-3) [3]
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