The scope of therapeutic options for the treatment of hepatocellular carcinoma (HCC) has recently been expanded by immunotherapeutic regimens. T cell-based therapies, especially in combination with other treatments have achieved far better outcomes compared to conventional treatments alone. However, there is an emerging body of evidence that eliciting T cell responses in immunotherapeutic approaches is insufficient for favorable outcomes. Immune responses in HCC are frequently attenuated in the tumor microenvironment (TME) or may even support tumor progress. Hence, therapies with immune checkpoint inhibitors or adoptive cell therapies appear to necessitate additional modification of the TME to unlock their full potential. In this review, we focus on immunotherapeutic strategies, underlying molecular mechanisms of CD8 T cell immunity, and causes of treatment failure in HCC of viral and non-viral origin. Furthermore, we provide an overview of TME features in underlying etiologies of HCC patients that mediate therapy resistance to checkpoint inhibition and discuss strategies from the literature concerning current approaches to these challenges.

Unconventional T cells (UTCs) are a heterogeneous group of T cells that typically exhibit rapid responses toward specific antigens from pathogens. Chronic hepatitis C virus (HCV) infection causes dysfunction of several subsets of UTCs. This altered phenotype and function of UTCs can persist over time even after direct‐acting antiviral (DAA)‐mediated clearance of chronic HCV. However, it is less clear if and how UTCs respond in acute, symptomatic HCV infection, a rare clinical condition, and if rapid DAA treatment of such patients reverses the caused perturbations within UTCs. Here, we comprehensively analyzed the phenotype and reinvigoration capacity of three major UTC populations, mucosal‐associated invariant T (MAIT) cells, γδ T cells, and CD4 and CD8 double‐negative αβ T cells (DNT cells) before, during, and after DAA‐mediated clearance of acute symptomatic HCV infection. Furthermore, MAIT cell functionality was systematically studied. We observed a reduced frequency of MAIT cells. However, remaining cells presented with a near‐to‐normal phenotype in acute infection, which contrasted with a significant dysfunction upon stimulation that was not restored after viral clearance. Notably, DNT and γδ T cells displayed a strong activation ex‐vivo in acute HCV infection, which subsequently normalized during the treatment. In addition, DNT cell activation was specifically associated with liver inflammation and inflammatory cytokines. Altogether, these data provide evidence that UTCs respond in a cell type‐specific manner during symptomatic HCV infection. However, even if early treatment is initiated, long‐lasting imprints within UTCs remain over time.

Chronic hepatitis C virus (HCV) infections compromise natural killer (NK)‐cell immunity. Direct‐acting antivirals (DAA) effectively eliminate HCV, but the long‐term effects on NK cells in cured patients are debated. We conducted a proteomic study on CD56+ NK cells of chronic HCV‐infected patients before and 1 year after DAA therapy. Donor‐variation was observed in NK‐cell proteomes of HCV‐infected patients, with 46 dysregulated proteins restored after DAA therapy. However, 30% of the CD56+ NK‐cell proteome remained altered 1 year post‐therapy, indicating a phenotypic shift with low donor‐variation. NK cells from virus‐negative cured patients exhibited global regulation of RNA‐processing and pathways related to “stimuli response”, “chemokine signaling”, and “cytotoxicity regulation”. Proteomics identified downregulation of vesicle transport components (CD107a, COPI/II complexes) and altered receptor expression profiles, indicating an inhibited NK‐cell phenotype. Yet, activated NK cells from HCV patients before and after therapy effectively upregulated IFN‐γ and recruited CD107a. Conversely, reduced surface expression levels of Tim‐3 and 2B4 were observed before and after therapy. In conclusion, this study reveals long‐term effects on the CD56+ NK‐cell compartment in convalescent HCV patients 1 year after therapy, with limited abundance of vesicle transport complexes and surface receptors, associated with a responsive NK‐cell phenotype.

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