Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages

Yan, Wenjiang; Liu, Xiao; Hong, Chun Pyo; Zhang, Hualin; Song, Xiaojia; Gao, Lifen; Liang, Xiaohong

doi:10.1136/gutjnl-2014-307671

Cited by 273 publications

(271 citation statements)

References 37 publications

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“…Blockade of TIM-3 in T cells cultured in vitro restored proliferation and IL-2 and IFN-γ production [9]. Recently, Yan et al showed that TIM-3 is highly expressed by monocytes and macrophage in HCC patients [46]. TIM-3 expression in macrophage was enhanced by TGF-β stimulation.…”

Section: Tim-3mentioning

confidence: 99%

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

2016

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Hepatocellular carcinoma (HCC) is a fatal disease with rising incidence in the world. For advanced HCC, sorafenib, a multikinase inhibitor, is the only systemic therapy with proven survival benefits. Sorafenib is a pan-VEGF receptor inhibitor, and thus many studies have focused its antivascular effects. But VEGF also acts as an immunosuppressive molecule. VEGF can inhibit maturation of dendritic cells, promote immune suppressive cell infiltration and enhance immune checkpoint molecules expression. On the other hand, potent VEGF inhibition may increase tumor hypoxia, which could hinder antitumor immunity or immunotherapy. Thus, achieving synergy when combining anti-VEGF therapy with immunotherapy may require proper polarization of the tumor microenvironment by dose titration or combination with other immunomodulating agents.

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Section: Tim-3mentioning

confidence: 99%

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

2016

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“…Of note, the role of Tim-3 in natural immunity is much more complex than its role in adaptive immunity. Recently, our laboratory has found that Tim-3 regulate the polarization of macrophages and accelerate the transformation of M1 macrophages into M2 macrophages, which then suppress the inflammatory response in HCC [44] . Together, these data indicate the complicated role of Tim-3 in regulating innate immune cells.…”

Section: Tim-3 and Monocytes/macrophagesmentioning

confidence: 99%

“…Specifically, elevated Tim-3 expression is negatively associated with tumor grade and patient survival. Moreover, ectopic expression of Tim-3 induces altered M2 activation, with a phenotype that promotes tumor development [44] . Our results further emphasize the critical role of Tim-3 as a new component in HCC progression.…”

Section: Tim-3 and Hccmentioning

confidence: 99%

Role of Tim-3 in hepatitis B virus infection: An overview

Liu

Gao

Liang

et al. 2016

WJG

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Hepatitis B virus (HBV) infection has received increasing public attention. hBV is the prototypical member of hepadnaviruses, which naturally infect only humans and great apes and induce the acute and persistent chronic infection of hepatocytes. A large body of evidence has demonstrated that dysfunction of the host anti-viral immune response is responsible for persistent HBV replication, unresolved inflammation and disease progression. Many regulatory factors are involved in immune dysfunction. Among these, T cell immunoglobulin domain and mucin domain-3 (Tim-3), one of the immune checkpoint proteins, has attracted increasing attention due to its critical role in regulating both adaptive and innate immune cells. In chronic HBV infection, Tim-3 expression is elevated in many types of immune cells, such as T helper cells, cytotoxic T lymphocytes, dendritic cells, macrophages and natural killer cells. Tim-3 over-expression is often accompanied by impaired function of the abovementioned immunocytes, and Tim-3 inhibition can at least partially rescue impaired immune function and thus promote viral clearance. A better understanding of the regulatory role of Tim-3 in host immunity during HBV infection will shed new light on the mechanisms of hBV-related liver disease and suggest new therapeutic methods for intervention.

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“…TIM-3 is an immune receptor discovered in 2002 that is expressed on a variety of immune cells including dendritic cells, macrophages, and T cells 20-22 . TIM-3 mediates its suppressive activity on immune cells via its ligands that include phosphatidylserine, CEACAM-1 and the widely expressed ligand galectin-9 23,24 .…”

Section: Introductionmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

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Tumor-infiltrating lymphocytes (TILs) are predominantly present in breast cancer patients with estrogen receptor negative tumors, among whom increasing levels correlate with favorable outcomes. Nevertheless, currently available immune checkpoint inhibitors appear to benefit only a small number of women with breast cancer. Upregulation of additional immune checkpoint markers is one mechanism of resistance to current inhibitors that might be amenable to targeting with newer agents. T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3) is an immune checkpoint receptor that is an emerging target for cancer immunotherapy. We investigated TIM-3 immunohistochemical expression in 3,992 breast cancer specimens assembled into tissue microarrays, linked to detailed outcome, clinico-pathological parameters and biomarkers including CD8, PD-1, PD-L1 and LAG-3. We scored and reported absolute counts for TIM-3+ intra-epithelial and stromal TILs (iTILs and sTILs), and find that breast cancer patients with TIM-3+ iTILs (≥ 1) represent a minority of cases (11%), with a predilection for basal-like breast cancers (among which 28% had TIM-3+ iTILs). TIM-3+ sTILs (≥ 2) represented 20% of cases and included more non-basal cases. The presence of TIM-3+ iTILs highly correlates with hematoxylin and eosin-stained stromal TILs and with other immune checkpoint markers (PD-1+ iTILs, LAG-3+ iTILs and PD-L1+ tumors). In prognostic analyses, early breast cancer patients with TIM-3+ iTILs have significantly improved breast cancer-specific survival whereas TIM-3+ sTILs did not reach statistical significance. In multivariate analyses, the presence of TIM-3+ iTILs is an independent favorable prognostic factor in the whole cohort as well as among ER negative patients. Our study supports TIM-3 as a target for breast cancer immunotherapy.

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Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages

Abstract: Tim-3 displays critical roles in microenvironment-induced activation and protumoral effects of TAMs in HCC. Interference of Tim-3 might be great potential in HCC therapy.

Cited by 273 publications

References 37 publications

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

Role of Tim-3 in hepatitis B virus infection: An overview

TIM-3 expression in breast cancer

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