CD8+ T Cell Responses during HCV Infection and HCC.

Maike Hofmann,Robert Thimme,Catrin Tauber,Nina Hensel

doi:10.3390/jcm10050991

Maike Hofmann, Robert Thimme + Show 2 more

Open Access

https://doi.org/10.3390/jcm10050991

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Abstract

Chronic hepatitis C virus (cHCV) infection is a major global health burden and the leading cause of hepatocellular carcinoma (HCC) in the Western world. The course and outcome of HCV infection is centrally influenced by CD8+ T cell responses. Indeed, strong virus-specific CD8+ T cell responses are associated with spontaneous viral clearance while failure of these responses, e.g., caused by viral escape and T cell exhaustion, is associated with the development of chronic infection. Recently, heterogeneity within the exhausted HCV-specific CD8+ T cells has been observed with implications for immunotherapeutic approaches also for other diseases. In HCC, the presence of tumor-infiltrating and peripheral CD8+ T cell responses correlates with a favorable prognosis. Thus, tumor-associated and tumor-specific CD8+ T cells are considered suitable targets for immunotherapeutic strategies. Here, we review the current knowledge of CD8+ T cell responses in chronic HCV infection and HCC and their respective failure with the potential consequences for T cell-associated immunotherapeutic approaches.

Highlights

Chronic hepatitis C virus infection is a major global health burden and the leading cause of hepatocellular carcinoma (HCC) in the Western world
We summarize the current knowledge of CD8+ T cell responses in Chronic hepatitis C virus (cHCV) infection and HCC with a special focus on their respective failure and the open questions since this sets the basis for the design of new or additive therapeutic strategies aiming at improving anti-viral and anti-tumoral CD8+ T cell responses
A deep understanding of the overall immune contexture including tumor-resident and tumor-specific immune cells is crucial to answer the following important questions in relation to the design of new or improved immunotherapeutic approaches: Which immune cells primarily respond to immunotherapy?; Which of the responding immune cells are beneficial, which are deleterious in the anti-tumor response? Or which immune cells support the anti-tumor CD8+ T cell response? Why are only some tumors accessible for immunotherapy?; and which T cell subsets mediate anti-tumoral activity in patients who respond to checkpoint blockade therapy?

Summary

Health Burdens Associated with the Liver

Chronic hepatitis C virus (cHCV) infection and hepatocellular carcinoma (HCC). affect the liver and represent major global health burdens. A first step in this direction was the recent identification of the HMG-box transcription factor TOX that regulates the epigenetic and transcriptional program in exhausted T cells in mouse models of chronic LCMV infection and cancer [60,61,62] and that is associated with the exhausted phenotype of HCV-specific CD8+ T cells [60] and PD1+ T cells in HCC [78] This observation of an association of TOX with exhausted T cell characteristics in cHCV and HCC highlights shared principles of CD8+ T cell dysfunction in both liver-associated diseases. The study of Flecken et al showed that CD8+ T cell responses specific for TAA are associated with prolonged progression-free survival in HCC patients [84].

Cells in HCC

Concluding Remarks

Findings

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