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Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide due to its emergence based on chronic liver disease. Thus, HCC can ultimately be caused by multiple factors, including chronic viral infection, alcohol abuse or obesity. Nevertheless, only a few therapeutic options are available, especially for patients in later stages of disease.1 Accordingly, prognosis of patients is often poor and HCC contributes disproportionately to cancer-related deaths worldwide. Thus, further research into HCC is required to inform the development of novel therapies as well as improvements to existing regimens. An important focus of current research into tumours in general, and HCC in particular, is the microenvironment in which development and progression of a tumour occurs. The tumour microenvironment comprises multiple cellular and non-cellular components and has been shown to be an important determinant of tumour progression, patient prognosis and thus also a determinant of therapeutic success in HCC and elsewhere.2 Indeed, some of the therapeutic effects of sorafenib, to date the only approved small-molecule inhibitor for treatment of advanced HCC, may be attributable to its effects on the tumour microenvironment.3 Among the different cell types found in the tumour microenvironment, macrophages, so-called tumour-associated macrophages (TAM), are among the most common. TAM typically differ from normal macrophages in their shift to an alternatively activated (M2) phenotype, induced by tumour-derived signals. They can be involved in multiple processes such as angiogenesis, metastasis, immunosuppression and tumour progression, especially by the secretion of a large variety of soluble molecules.4 However, to date little is known about the regulation or phenotype of TAM in HCC. This is the focus of the work by Yan et al 5 in this issue of Gut, who investigate the expression of T cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) on macrophages and monocytes in patients with HCC. Tim-3 is a cell-surface protein well known for its role in the inhibition of T cell immunity in HCC as well as in other settings6 (Figure 1A). However, despite its name, Tim-3 expression matters also on other cell types, such as macrophages, where it appears to be involved in a variety of processes.7 In the context of these data, results reported by Yan et al5 in the current issue bring to light the role of Tim-3 as a new mechanism linking TAM and HCC progression. The authors first analysed Tim-3 expression in peripheral monocytes, demonstrating not only a higher expression in monocytes from patients with HCC with respect to controls, but also a correlation with tumour grades. Interestingly, this Tim-3 expression was higher in M2 monocytes, those traditionally described as promoters of tumour progression. More importantly, analysis of Tim-3 in macrophages from tumour samples confirmed its upregulation, as compared with non-tumour tissue, correlating with patient survival. To determine whether Tim-3 expression was a mere marker of tumour progression or whether it could also be considered as a driver in this mechanism, the authors moved to a murine HCC in vivo model. In this setting, administration of macrophages with silenced expression of Tim-3 resulted in decreased tumour growth, suggesting that Tim-3 expression in TAM may promote HCC growth in vivo. In a next series of experiments, the authors analysed the factors responsible for inducing Tim-3 in TAM. It has been described that many factors overexpressed in the tumour microenvironment may modulate expression of molecules relevant for tumour progression, thus creating a positive feedback loop, which reinforces tumour growth. The authors first demonstrated that tumour-conditioned media not only induced TAM polarisation towards an M2 phenotype but also upregulated Tim-3 expression. Second, they characterised that this TAM polarisation was dependent on transforming growth factor-β (TGF-β), a cytokine with well-described protumorigenic properties. Finally, they showed that Tim-3 was involved in M2 polarisation in TGF-β-dependent and TGF-β-independent pathways, promoting tumour growth through the nuclear factor-κB/interleukin (IL)-6 axis. Altogether, these results describe a new link between TAM and HCC progression through Tim-3 expression. Although most experiments reported by Yan et al elucidating the role of Tim-3 in tumour progression either directly measure tumour load in vivo or check tumour cell proliferation and invasiveness, indicating a direct effect on tumour cells, it is important to highlight also the role of Tim-3 as an immunomodulatory molecule. Despite different functional effects assigned to Tim-3 in terms of immune responses, it is in general recognised as an immunosuppressive molecule. Indeed, in patients with HCC, Tim-3 is not only expressed in TAM, determining their polarisation and the concomitant production of important cytokines for immune activation/suppression like IL-12 and IL-10. As shown by Yan et al and others, it is also highly upregulated in peripheral T cells, where it is considered a marker of lymphocyte exhaustion and an immune checkpoint receptor demonstrated in chronic viral infection and cancer.6–9 Accordingly, Tim-3 has emerged as a new target in cancer immunotherapy. Although Tim-3 silencing/blockade experiments shown by Yan et al are only related to its expression in TAM, a general blockade, as currently used in cancer therapy with antibodies against other checkpoint inhibitors, would presumably provide a stronger benefit since it may simultaneously block the different Tim-3-dependent pathways that collaborate in tumour progression (Figure 1B). Indeed, preclinical experiments of Tim-3 blockade in different murine tumour models have shown promising results, with a remarkable synergy with programmed death-1 (PD-1) blockade, a recently approved therapy.9 ,10 Finally, it has to be noted that as opposed to cytotoxic T-lymphocyte antigen-4 and PD-1, molecules targeted by currently approved antibodies, the lack of Tim-3 is not associated with autoimmune effects, suggesting that a therapy based on its blockade is less likely to involve immune-associated toxic events.10 Thus, results reported by Yan et al not only help to elucidate new mechanisms of HCC progression but also describe a target, which opens new therapeutic possibilities for these patients.
Contributors TF and PS contributed equally.
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.
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