Alterations in Hepatocellular Carcinoma-Specific Immune Responses Following Hepatitis C Virus Elimination by Direct-Acting Antivirals

Abstract

Direct-acting antivirals (DAAs) have recently revolutionized the eradication of chronic hepatitis C virus (HCV) infection. However, the effects of DAAs on the development of hepatocellular carcinoma (HCC) remain unknown. Therefore, the present study aimed to investigate immune responses to HCC influenced by DAAs in HCV-infected patients and elucidate the underlying mechanisms. We compared immune responses to 19 different HCC-related tumor-associated antigen (TAA)-derived peptides and host immune cell profiles before and 24 weeks after a treatment with DAAs in 47 HLA-A24-positive patients. The relationships between the different immune responses and phenotypic changes in immune cells were also examined. The treatment with DAAs induced four types of immune responses to TAAs and markedly altered host immune cell profiles. Prominently, reductions in the frequencies of PD-1+CD4+ and PD-1+CD8+ T cells by DAAs were associated with enhanced immune responses to TAAs. The HCV F protein was identified as contributing to the increased frequency of PD-1+ T cells, which may be decreased after eradication by DAAs. DAAs altered the immune responses of patients to HCC by decreasing the frequency of PD-1-expressing CD4+ and CD8+ T cells.

Programmed cell death-1 is involved with peripheral blood immune cell profiles in patients with hepatitis C virus antiviral therapy

“…There was little correlation between TBX21 and IFN signaling-related genes in this study. Our findings showed that TBX21 was important for PD-1 related signaling involved in HCV F protein-mediated immune responses [ 29 ]. The results also showed that TBX21 was involved with PD-1, including in immune checkpoint signaling, but did not lead directly to IFN-related responses.…”

“…Thus, TBX21 is closely associated with SVR or non-SVR patterns induced by any antiviral drugs including DAAs or IFN. We analyzed this factor in detail with respect to the immune response that leads to hepatocarcinogenesis [ 29 ].…”

Imprinted immune abnormalities in liver transplant patients cured of hepatitis C with antiviral drugs

“…They are not specific for HCV Ag and are important for microbial defense and cancer immune surveillance. A previous study of HCV-infected patients with HCC found that HCV cure decreased PD-1 expression on T cells and enhanced responses to tumor-derived peptides in some cases 17 . B cell abnormalities are common during chronic HCV infection 18,19 and do not completely remit in many patients cured of HCV 20,21 .…”

“…A previous study of HCV-infected patients with HCC found that HCV cure decreased PD-1 expression on T cells and enhanced responses to tumor-derived peptides in some cases. [17] B cell abnormalities are common during chronic HCV infection [18,19] and do not completely remit in many patients cured of HCV. [20,21] In addition, the mucosal-associated invariant T cells are not restored [22] and the repertoire diversity of natural killer cells remains altered, [23] although these cells become more functional and responsive to stimulation.…”