Tim-3 expression in tumour-associated macrophages: a new player in HCC progression

T Flecken, P Sarobe - Gut, 2015 - gut.bmj.com
T Flecken, P Sarobe
Gut, 2015gut.bmj.com
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 …
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 tumourassociated 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 settings 6(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 al 5 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
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