Antitumor CD8+T cells in hepatocellular carcinoma: Present but exhausted

H epatocellular carcinoma (HCC) is the second leading cause of global cancer deaths and the incidence is rising. Advances in medical treatment have resulted in improved survival for many common malignancies, but not HCC. The lack of curative treatments and consequent dismal survival rates make elucidating HCC biology and translating this into effective treatments a priority. There is good evidence that HCC stimulates an immune response, making immunotherapy in which the host’s immune system is stimulated to attack the cancer a potential option. However, despite efficacy in animal models, most clinical trials of tumor immunotherapy have been disappointing. The article from Robert Thimme’s group in this issue highlights mechanisms that inhibit effective antitumor immunity in HCC and suggests immunotherapeutic options against a formidable foe. The host immune system has the potential to recognize a wide range of tumor-associated antigens (TAA) including alpha-fetoprotein (AFP). Moreover, there is emerging evidence that the presence of TAA-specific T cells is associated with an improved response to dendritic cell (DC) vaccination and better prognosis. However, despite mounting a detectable immune response, tumor progression frequently occurs, and understanding why the immune response fails to control the tumor is a crucial step if immunotherapy is to become clinically effective. Many mechanisms have been implicated in cancer immune evasion. These include down-regulation of major histocompatility complex (MHC) molecules and TAA on tumor cells, inhibition of effector immune cells functions, the recruitment and induction of immunosuppressive immune cells, and the disruption of effective tumor antigen presentation as a consequence of reduced costimulatory molecule expression and interference of antigen processing by DC (Fig. 1). In this month’s issue of HEPATOLOGY, Flecken et al. report new findings on the antitumor response in HCC with important therapeutic implications. The authors describe a subset of CD8T cells specific for the TAAs AFP, glypican-3 (GPC-3), melanomaassociated gene-A1 (MAGE-A1), and New Yorkesophageal squamous cell carcinoma-1 (NY-ESO-1) in the blood, liver, and tumors of patients with HCC, and quantified the magnitude and breadth of the antitumor CD8T-cell response. Previous studies have reported an association between the strength of the antitumor T-cell response and patient survival and the present work illustrates that a broad immune response early in disease is associated with a better prognosis. This has implications for the development of therapeutic vaccines. Many vaccine trials have used a specific antigen or antigenic epitope to prime T-cell responses. However, the identification of multiple immunodominant epitopes across different tumor antigens suggests that vaccines should incorporate several antigens if they are to be effective. In the context of DC-based vaccination, this study supports the use of tumor lysate to pulse DCs based on the notion that multiple tumor lysate proteins favor the development of a broader antitumor immune response. The authors go on to demonstrate that TAA-specific CD8T cells expanded from the blood of patients with HCC have markedly impaired IFN-c secretion and cytolytic activity. Interestingly, the same patients had preserved effector CD8T cells against Epstein-Barr virus (EBV) and cytomegalovirus (CMV), suggesting that this is a specific tumor effect. This is important because it shows that the TAA-specific CD8T cells are present, they have not been deleted, and thus it is potentially possible to restore their effector function. However, to do this it is important to understand the underlying mechanisms responsible for their dysfunction. These include T-cell exhaustion as a consequence Abbreviations: AFP, alpha-fetoprotein; CTLA-4, cytotoxic T-lymphocytes antigen-4; DC, dendritic cell; HCC, hepatocellular carcinoma; IFN-g, interferon gamma; MDSC, myeloid-derived suppressive cells; MHC, major histocompatility complex; PD-1, programmed death receptor-1; TAA, tumor associated antigens; TAM, tumor-associated macrophages; Tregs, regulatory T cells. Address reprint requests to: David H. Adams, FRCP, F.Med.Sci., Professor of Hepatology, National Institute for Health Research Biomedical Research Unit, University of Birmingham, Birmingham, UK. E-mail: d.h. adams@bham.ac. uk. Received September 4, 2013; accepted September 25, 2013. Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26779 Potential conflict of interest: Nothing to report.