The Role of TIM-3 in Hepatocellular Carcinoma: A Promising Target for Immunotherapy?

Ganjalikhani‐Hakemi, Mazdak; Jafarinia, Morteza; Azizi, Mahdieh; Rezaeepoor, Mahsa; Isayev, Orkhan; Bazhin, Alexandr V.

doi:10.3389/fonc.2020.601661

Cited by 36 publications

(21 citation statements)

References 83 publications

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“…In addition to antibodies against CTLA-4 and PD-1/PD-L1, checkpoint inhibitor targeting TIM-3 is another potential and promising candidate of immunotherapy for cancer treatment[ 272 , 299 ]. TIM-3, a type I surface glycoproteins encoded by the gene on chromosome 5q33.2, was first discovered in 2001 and identified as an immune checkpoint that specifically expressed on interferon-γ-secreting CD4(+) T helper 1 and CD8(+) T cytotoxic cells in both mice and humans[ 300 , 301 ]. TIM-3 acts as a negative regulator of T cell function by triggering cell death upon interaction with its ligand, galectin-9.…”

Section: Challenges Of Treating Hcc In Patients With Renal Dysfunctionmentioning

confidence: 99%

Hepatocellular carcinoma in patients with renal dysfunction: Pathophysiology, prognosis, and treatment challenges

Yeh¹,

Chiang²,

Yen³

2021

WJG

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The population of patients with hepatocellular carcinoma (HCC) overlaps to a high degree with those for chronic kidney disease (CKD) and end-stage renal disease (ESRD). The degrees of renal dysfunction vary, from the various stages of CKD to dialysis-dependent ESRD, which often affects the prognosis and treatment choice of patients with HCC. In addition, renal dysfunction makes treatment more difficult and may negatively affect treatment outcomes. This study summarized the possible causes of the high comorbidity of HCC and renal dysfunction. The possible mechanisms of CKD causing HCC involve uremia itself, long-term dialysis status, immunosuppressive agents for postrenal transplant status, and miscellaneous factors such as hormone alterations and dysbiosis. The possible mechanisms of HCC affecting renal function include direct tumor invasion and hepatorenal syndrome. Finally, we categorized the risk factors that could lead to both HCC and CKD into four categories: Environmental toxins, viral hepatitis, metabolic syndrome, and vasoactive factors. Both CKD and ESRD have been reported to negatively affect HCC prognosis, but more research is warranted to confirm this. Furthermore, ESRD status itself ought not to prevent patients receiving aggressive treatments. This study then adopted the well-known Barcelona Clinic Liver Cancer guidelines as a framework to discuss the indicators for each stage of HCC treatment, treatment-related adverse renal effects, and concerns that are specific to patients with pre-existing renal dysfunction when undergoing aggressive treatments against CKD and ESRD. Such aggressive treatments include liver resection, simultaneous liver kidney transplantation, radiofrequency ablation, and transarterial chemoembolization. Finally, focusing on patients unable to receive active treatment, this study compiled information on the latest systemic pharmacological therapies, including targeted and immunotherapeutic drugs. Based on available clinical studies and Food and Drug Administration labels, this study details the drug indications, side effects, and dose adjustments for patients with renal dysfunction. It also provides a comprehensive review of information on HCC patients with renal dysfunction from disease onset to treatment.

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Section: Challenges Of Treating Hcc In Patients With Renal Dysfunctionmentioning

confidence: 99%

Hepatocellular carcinoma in patients with renal dysfunction: Pathophysiology, prognosis, and treatment challenges

Yeh¹,

Chiang²,

Yen³

2021

WJG

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“…TIM-3 was initially identified as a T cell marker for Th1 and CD8 + T cells. It was later shown that TIM-3 is expressed by human Th1 and Th17 cells and also other immune cells encompassing dendritic cells (DCs), macrophages, and natural killer (NK) cells (Ganjalikhani Hakemi et al, 2020). TIM-3 is expressed on activated T cells, and its signaling on cytotoxic T cells leads to reduction in proliferation, decreased production of effector cytokines and apoptosis of effector T cells.…”

Section: Introductionmentioning

confidence: 99%

TIM-3 and CEACAM1 are Prognostic Factors in Head and Neck Squamous Cell Carcinoma

Yang

Zeng

et al. 2021

Front. Mol. Biosci.

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Background: T-cell Immunoglobulin and Mucin domain-containing molecule-3 (TIM-3) is a new immune checkpoint molecule which plays important and complex roles in regulating immune responses and in inducing immune tolerance. TIM-3 is expressed on activated T cells and its signaling on cytotoxic T cells leads to T cell exhaustion which is mediated by carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on tumor tissues and/or tumor infiltrating lymphocytes (TILs).Methods: In the present study, we investigated TIM-3 and CEACAM1 immunohistochemical expression in 80 head and neck squamous cell carcinoma (HNSCC) specimens, linked to detailed outcome, clinic-pathological parameters. Here we reported scores and absolute counts of TIM-3+/CEACAM1+ TILs, and evaluated the expression of CEACAM1 on tumor tissues.Results: The results showed that more TIM-3+ TILs infiltration correlated with poorer overall survival (p < 0.001), as did the presence of CEACAM1 on cancer cells (p < 0.001) and CEACAM1+ TILs in tumor microenvironment (p = 0.015). Multivariate Cox regression analysis revealed that high TIM-3+ TILs may be considered as an independent prognostic factor of poor disease outcome (hazard ratio, 2.066; 95% confidence interval, 1.027–4.159; p = 0.042), as well as cancer cells expressed CEACAM1 level (hazard ratio, 5.885; 95% confidence interval, 2.832–12.230; p < 0.001).Conclusion: Our results indicate that expression of TIM-3 and CEACAM1 may represent a highly dysfunctional population of T cells. Our current findings suggest both of them were valuable predicting markers that might provide help for clinicians to design effective immunotherapeutic regimen against head and neck carcinoma.

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“…SREBP-1 (Sterol Regulatory Element Binding Protein-1) and GLUT-1 are important regulators of cellular material and energy metabolism ( 42 – 45 ) for modulating the microenvironment of tumor cells. Therefore, it is necessary to further examine the participation of the aberrant metabolism of malignant tumor cells in the progress or resistance of cancer cells to antitumor agents ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

MDM2 Binding Protein Induces the Resistance of Hepatocellular Carcinoma Cells to Molecular Targeting Agents via Enhancing the Transcription Factor Activity of the Pregnane X Receptor

Jiang

Han³

et al. 2021

Front. Oncol.

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The MDM2 binding protein (MTBP) has been considered an important regulator of human malignancies. In this study, we demonstrate that the high level of MTBP’s endogenous expression is correlated with poor prognosis of advanced hepatocellular carcinoma (HCC) patients who received sorafenib. MTBP interacted with the Pregnane X receptor (PXR) and enhanced the transcription factor activity of PXR. Moreover, MTBP enhanced the accumulation of PXR in HCC cells’ nuclear and the recruitment of PXR to its downstream gene’s (cyp3a4’s) promoter region. Mechanically, the knockdown of MTBP in MHCC97-H cells with high levels of MTBP decelerated the clearance or metabolism of sorafenib in HCC cells and led to the resistance of HCC cells to sorafenib. Whereas overexpression of MTBP in in MHCC97-L cells with low levels of MTBP showed the opposite trend. By establishing the interaction between MTBP and PXR, our results indicate that MTBP could function as a co-activator of PXR and could be a promising therapeutic target to enhance the sensitivity of HCC cells to molecular targeting agents.

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The Role of TIM-3 in Hepatocellular Carcinoma: A Promising Target for Immunotherapy?

Cited by 36 publications

References 83 publications

Hepatocellular carcinoma in patients with renal dysfunction: Pathophysiology, prognosis, and treatment challenges

Hepatocellular carcinoma in patients with renal dysfunction: Pathophysiology, prognosis, and treatment challenges

TIM-3 and CEACAM1 are Prognostic Factors in Head and Neck Squamous Cell Carcinoma

MDM2 Binding Protein Induces the Resistance of Hepatocellular Carcinoma Cells to Molecular Targeting Agents via Enhancing the Transcription Factor Activity of the Pregnane X Receptor

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