Immune evasion is one of the hallmark features acquired during the development and progression of cancer.1 Advances in our understanding of tumor immunology continue to provide important insights into the nature of the tumor-host immune response and its impact on cancer pathogenesis. The composition of the immune response in the tumor microenvironment can influence tumor immunity, tolerance, therapy, and clinical outcome. The tumor microenvironment is comprised of tumor cells, the local cytokine environment, and immune cell subsets. Tumors use a number of immune suppressive mechanisms to shape the immune microenvironment to favor tolerance over immunity and promote tumor growth.

Compelling clinical data in patients with hepatocellular carcinoma (HCC) suggests that the evolution of HCC induces several immune suppressor mechanisms. These different cellular mechanisms of immunosuppression include soluble factors and immune cell subsets such as: elevations of CD4+CD25+ regulatory T cells (Tregs); impaired dendritic cells (DCs); induction of myeloid-derived suppressor cells (MDSC); generation of inhibitory macrophages; and production of immunosuppressive cytokines (transforming growth factor beta [TGF-β], prostaglandins, soluble CD25).2–5 All these factors in concert negatively impact the beneficial antitumor immune responses by suppressing natural killer (NK) cells and CD4+ and CD8+ T cells (Fig. 1).7, 8 In the current issue of Hepatology, the study by Fu et al.9 presents work describing a new subset of CD4+ T cells: CD4+ cytotoxic T cells (CTL) in HCC. The authors evaluated CD4+ CTLs in a large series of patients with HCC and chronic hepatitis B virus (HBV) infection, and found clinically important correlations between CD4+ CTL, survival, and recurrence rates in patients with HCC.

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Figure 1. Immune cell factors involved in the immunopathogenesis of hepatocellular carcinoma (HCC) and the balance between tumor tolerance and immunity in the tumor microenvironment. These immune factors are important to consider when developing novel therapeutic targets. APC, antigen-presenting cells; MDSC, myeloid-derived suppressor cells; DC, mature dendritic cells; sCD25, soluble CD25; NK, natural killer cells; CTL, cytotoxic T cells.

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CD4+ T cells are a diverse and growing group of distinct cell subsets with different function and cytokine secretion patterns. These different CD4+ T-cell subsets: T helper 1 (TH1), TH2, TH17, and Tregs, carry out specialized immunoregulatory functions to either enhance or inhibit immune responses. In the study by Fu et al. we learn that in addition to the more established subsets of CD4+ T cells, CD4+ CTLs also play a role in HCC immunopathogenesis. CD4+ CTLs are a population of T cells that express granzyme and perforin that are effectors in mediating the cytotoxic activity on target cells.10 CD4+ CTLs kill target tumor cells by way of HLA Class II molecules and they are also found in the circulation only in disease states including autoimmune disease or viral infections.11 The study by Fu et al. provides the first report of decreased CD4+ CTLs frequency within the liver tumor tissue compared to nontumor liver regions in patients with HBV-related HCC. The relative reductions of CD4+ CTLs within the tumor compared to nontumor areas demonstrate the immunosuppressive state of the tumor microenvironment within HCC. The finding of a CD4 T-cell subset with CTL features not only adds to the complexity of the immune infiltrate in HCC but also provides insight into the plasticity of CD4+ T cells in tumor immunity.

HCC is a common, often lethal, complication that while most often emerges in the setting of cirrhosis it can occur even in the absence of cirrhosis in chronic HBV. Most patients present with advanced tumors when treatment options are limited, despite the vigorous and early screening recommended in the American Association for the Study of Liver Diseases (AASLD) practice guidelines.12 Early detection of HCC development is a difficult clinical challenge. Current clinical practice for HCC screening includes alpha-fetoprotein (AFP) monitoring and liver ultrasound that have limited sensitivity, as AFP levels do not reliably correlate with disease, survival, or recurrence. This substandard sensitivity underlines the need for a biomarker that is able to detect early stage HCC, tumor progression, and/or recurrence after surgical treatment. Thus, it is not unexpected that biomarker discovery is a hot topic in HCC research. Several biomarkers are under investigation in HCC, including glycipan-3, des-gamma-carboxyprothrombin, and micro-RNAs; however, none of these are sufficiently sensitive and/or specific to warrant clinical utility. The data of Fu et al. indicate that peripheral CD4+ CTLs might serve as biomarkers in HCC progression. Data in this article indicate that the percentage of circulating CD4+ CTLs was higher in HCC patients compared to chronic HBV-infected patients or normal control subjects. Interestingly, however, a progressive reduction was found in the frequency of circulating CD4+ CTLs during HCC disease progression. This reduction in CD4+ CTLs occurred in the peripheral circulation as well as in the liver, both in the tumor infiltrating and noninfiltrating lymphocyte populations. This negative correlation between the frequency of CD4+ CTLs in both the periphery and liver and tumor burden likely reflects the development of tumor-related immune suppression with HCC progression.

Not only the number of CD4+ CTLs but their functions were also altered in HCC. While granzyme A, B, and perforin expression were all higher in HCC patients compared to chronic HBV infection or normal controls, there was a significant reduction in all of these enzymes with HCC progression. Because CD4+ CTLs have a direct tumor-killing function by way of granzyme and perforin, the reduction in the number and killing capacity of CD4+ CTLs with advancing stage of HCC likely indicates the diminishing capacity of the immune system in antitumor surveillance and defense. CD4+ CTLs may have utility as a sensitive biomarker of HCC progression and/or recurrence. Lower numbers of CD4+ CTLs predicted poor survival in HCC patients.

Regulation of the frequency and function of the CD4+ CTL population is complex and, among various factors, Fu et al. show that Tregs play a role. An inverse relationship between Tregs and CD4+ CTLs was found in HCC patients and, importantly, a mechanistic link was discovered between Tregs and CD4+ CTLs. The authors demonstrate that Tregs mediate the reduction in the CD4+ CTL population as well as the functional impairment with reduced granzyme and perforin expression. In addition, another potential regulatory pathway is identified by showing that CD4+ CTLs express high levels of programmed death-1 (PD-1) on their cell surface. Overcoming negative immune regulatory pathways such as Tregs and PD-1 will be critical to improve the current therapies for advanced HCC, which are marginally effective. Recently, immune activating strategies targeting negative immune checkpoints (CTLA-4 and PD-1) demonstrated clinical success.13 Further research into the potential mechanisms regulating CD4+ CTL responses may provide novel therapeutic targets that are an urgent need for patients with HCC.

Immunity plays a fundamental role in cancer development and progression. Emerging evidence demonstrates a role for CD4+ CTLs in HCC immune pathogenesis. CD4+ CTLs contribute to immune escape by their progressive decline in frequency within the liver tumor and periphery as the tumor grows. The decline in frequency and also function of CD4+ CTLs in HCC occurs with advancing tumor burden and is related to an increase in Treg-mediated suppression. Results from the study by Fu et al. and other clinical studies strongly suggest that we should focus on harnessing the immune response to treat HCC. Progress on the treatment of HCC will come with therapeutic strategies that amplify immune activation of tumor-specific immunity, counteract immune suppressive mechanisms, and lead to sustained antitumor immune responses.


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