Targeting chemokines as a therapeutic option for hepatocellular carcinoma: A reality or just a fantasy?

Hepatocellular carcinoma (HCC) is the fifth most common cancer1 and the third leading cause of cancer-related death worldwide,2 with a 5-year survival rate of less than 5%. The estimated annual incidence of HCC is 626 000 cases,2 which will continue to rise in Western countries such as Australia, USA and UK, most likely due to the worldwide spread of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections.2 Surgical resection and liver transplantation are the most effective treatment options so far if the tumors are caught at a very early stage, of small size, and without distant metastasis.3-5 However, less than 12% of patients are suitable for these treatments, and the high recurrence rate, poor quality of life following surgical procedures, donor shortage, and the necessity of long-term usage of immunosuppressive agents following transplantation are important limiting factors for these procedures. Local ablative therapy (such as radiofrequency ablation, cryotherapy, and ethanol injection), systemic chemotherapy, internal radiation therapy, and transarterial chemoembolization are also frequently used, but they are generally palliative measures. Therefore, exploration of alternative therapeutic approaches for HCC is a critical challenge that we are all facing. In order to develop a more effective therapy against HCC, we must seek a better understanding of the pathogenesis and molecular biology of HCC development. Increasing evidence has suggested that chronic inflammatory changes are causatively linked to the development of certain cancers such as colorectal cancer and liver cancer. However, local inflammatory changes in tumor tissues may be a reflection of the host immune reaction against tumors, and thus are associated with a favorable prognosis. This has been observed in many tumors such as melanoma, ovarian cancer, and colorectal carcinoma. In HCC, patients with surgical specimens showing significant T cell infiltration were found to have a better prognosis.6, 7 Indeed, infiltration of tumor tissues by inflammatory cells, especially lymphocytes, is one of the important mechanisms of host immune reaction against tumors. The lymphocytes infiltrating the tumor tissues are termed tumor-infiltrating lymphocytes (TILs). These TILs form part of the tumor microenvironment in combination with tumor cells, stromal fibroblasts, endothelial cells, macrophages and dendritic cells. TILs consist of several types of immune cells including helper and suppressor T lymphocytes, B lymph cells, natural killer cells, and macrophages. T cells (mostly CD8+ T cells) are the predominant component of TILs,6 although more than 96% of them are quiescent. TILs also contain a subpopulation of suppressive CD4+/CD25+ regulatory T cells (T-regs), which suppress the proliferation and activity of effector CD4+ and CD8+ T cells and are thus linked to self-tolerance of the normal cells and the host antitumor immune responses.8-10 Tumor-infiltrating lymphocytes and other cells in the tumor microenvironment produce a variety of cytokines, chemokines and growth factors. These biological products participate in multiple biological processes, such as cell differentiation, receptor activation, and cell survival. The interaction between cytokines, chemokines, growth factors and their receptors forms a comprehensive network in tumors.11 Chemokines are structurally related cytokines secreted by multiple cell types. They are important mediators of TILs recruiting and trafficking.12 Most chemokines also play important roles in carcinogenesis, angiogenesis, tumor invasion and metastasis, as well as host immune response against tumors.12-15 The biological effects of chemokines in host immune responses are largely through promotion of chemotaxis and activation of specific effector leukocyte subpopulations (such as TILs, natural killer cells and natural killer T cells). Thus, chemokines and their receptors may represent potentially useful therapeutic targets for drug development in cancer therapy.11, 12,16 A better understanding of molecular mechanisms involved in the chemokine-induced immune response may facilitate the development of chemokine-based cancer therapy. Over 40 known chemokines have been identified so far and they are grouped into four classes: XC, CC, CXC, and XC3C chemokines. In this issue of the Journal, Hirano et al.17 report the relationship between TILs and the expression of the chemokines in HCC tumor tissues using two complementary methods: immunohistochemistry and real-time polymerase chain reaction assay (RT-PCR). The authors investigated the expression of RANTES (CC chemokines), IL-8, ENA-78, IP-10 and Mig (all CXC chemokines) in 44 HCC tissues. The authors found that TILs in HCC tissues are predominantly CD8+ T lymphocytes. The number of TILs in HCC tissues was significantly correlated with the expression level of Mig/IP-10. Also noted was a close correlation between the expression of interferon-γ mRNA and Mig/IP-10 mRNA, suggesting interferon-γ might be responsible for the production of the tested chemokines. These findings allow us to infer that these chemokines promote TILs recruitment to HCC tissues where they exert their anticancer effect. Bearing this in mind, we can speculate that intratumoral injection of certain chemokines such as interferon-γ may lead to an induction of Mig and IP-10, which then recruit cytotoxic T lymphocytes to the tumor sites where they suppress the tumor progression. This speculation may be too simplistic at this stage. Chemokines are just one part of the complex network in anticancer mechanism. Communication and interaction between various chemokines and other immunological effectors are just as important in the immune response against tumors. Whether interferon-γ interacts with Mig and IP-10 and how such interaction, if any, results in recruitment and subsequent functioning of TILs in the tumor microenvironment are some of the important issues awaiting clarification. From a clinicopathological perspective, does the discovered association between TILs and expression of Mig and IP-10 correlate with tumor differentiation status, α-fetoprotein levels, portal vein invasion, distant metastasis, tumor recurrence, and overall survival of HCC patients? Clarification of these issues would be very helpful in answering the question of whether chemokines are of potentially benefit in designing immunotherapy for HCC. To be an effective immunotherapy for cancer, three important requirements have to be met:8, 18 (i) there has to be a sufficient number of avid tumor-reactive lymphocytes in the tumor-bearing host; (ii) these lymphocytes must have a sufficient capability of reaching and extravasating at the tumor site; and (iii) these intratumoral lymphocytes are active enough to destroy cancer cells. Although clinical trials for various immunotherapeutic strategies have been initiated and some showed promising results,8, 9,19 the overall response to immunotherapy for HCC remains unsatisfactory. The findings of the study by Hirano et al. have important implications in understanding the immunopathogenesis and designing a novel therapeutic strategy for HCC. This study triggers a necessity for further work exploring the feasibility and efficacy of using chemokine ligands/receptors as targets for cancer immunotherapy. However, other issues such as how to achieve sufficient expansion and recruitment of activated tumor-specific cytotoxic T cells to tumors, how antigen expression and presentation can be intensified, and how local immunosuppressive factors or cells can be depleted will also need to be answered before an efficacious immunotherapy can be developed for HCC.