Clinical impact of herpesvirus entry mediator expression in human hepatocellular carcinoma

Hokuto, Daisuke; Sho, Masayuki; Yamato, Ichiro; Yasuda, Satoshi; Obara, Shinsaku; Nomi, Takeo; Nakajima, Yoshiyuki

doi:10.1016/j.ejca.2014.11.004

Cited by 53 publications

(49 citation statements)

References 40 publications

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“…HVEM also exists as a soluble form in the circulation . Preclinical and clinical studies have suggested that dysregulation of the HVEM network contributes to multiple inflammatory and infectious diseases . Currently, the expression pattern and roles of the HVEM axis in AH pathogenesis are unknown.…”

Section: Discussionmentioning

confidence: 99%

“…(34) Preclinical and clinical studies have suggested that dysregulation of the HVEM network contributes to multiple inflammatory and infectious diseases. (33,(35)(36)(37) Currently, the expression pattern and roles of the HVEM axis in AH pathogenesis are unknown. Here, we found that expression of both soluble and membrane forms of the HVEM network were highly dysregulated in patients with AH.…”

Section: Discussionmentioning

confidence: 99%

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Immune Checkpoint Axes Are Dysregulated in Patients With Alcoholic Hepatitis

Li¹,

Xia²,

Yang³

et al. 2020

Hepatol Commun

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Alcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in some heavy drinkers. The immune system in patients with AH is hyperactive and yet dysfunctional. Here, we investigated whether this immune‐dysregulated state is related to the alcoholic impact on immune checkpoints (ICPs). We used multiplex immunoassays and enzyme‐linked immunosorbent assay to quantify plasma levels of 18 soluble ICPs (sICPs) from 81 patients with AH, 65 heavy drinkers without liver diseases (HDCs), and 39 healthy controls (HCs) at baseline, 33 patients with AH and 32 HDCs at 6‐month follow‐up, and 18 patients with AH and 29 HDCs at 12‐month follow‐up. We demonstrated that baseline levels of 6 sICPs (soluble T‐cell immunoglobulin and mucin domain 3 [sTIM‐3], soluble cluster of differentiation [sCD]27, sCD40, soluble Toll‐like receptor‐2 [sTLR‐2], soluble herpesvirus entry mediator [sHVEM], and soluble lymphotoxin‐like inducible protein that competes with glycoprotein D for herpes virus entry on T cells [sLIGHT]) were up‐regulated, while 11 sICPs (soluble B‐ and T‐lymphocyte attenuator [sBTLA], sCD160, soluble cytotoxic T‐lymphocyte‐associated protein 4 [sCTLA‐4], soluble lymphocyte‐activation gene 3 [sLAG‐3], soluble programmed death 1 [sPD‐1], sPD ligand 1 [sPD‐L1], sCD28, soluble glucocorticoid‐induced tumor necrosis factor receptor‐related protein [sGITR], sGITR ligand [sGITRL], sCD80, and inducible T‐cell costimulator [sICOS]) were down‐regulated in patients with AH compared to HDCs. The up‐regulated sICPs except sLIGHT and down‐regulated sCD80, sCD160, sCTLA‐4, and sLAG‐3 correlated positively or negatively with AH disease severity, bacterial translocation, and inflammatory factors. At follow‐up, abstinent patients with AH still had higher levels of several sICPs compared to HDCs. We also compared expression of 10 membrane‐bound ICPs (mICPs) on peripheral blood mononuclear cells (PBMCs) from patients with AH and HCs by flow cytometry and found that several mICPs were dysregulated on blood cells from patients with AH. The function and regulation of sICPs and mICPs were studied using PBMCs from patients with AH and HCs. Recombinant sHVEM affected tumor necrosis factor (TNF)‐α and interferon‐γ production by T cells from patients with AH and HCs. Conclusion: Both sICPs and mICPs were dysregulated in patients with AH, and alcohol abstinence did not fully reverse these abnormalities. The HVEM axis plays a role in regulating T‐cell function in patients with AH.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immune Checkpoint Axes Are Dysregulated in Patients With Alcoholic Hepatitis

Li¹,

Xia²,

Yang³

et al. 2020

Hepatol Commun

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“…We analyzed the impact of TIL to predict the outcome of patients with HBV‐positive or NBNC hepatitis, and find a significant association between high TIL and good OS, and low recurrence rate. To evaluate just TIL from HE staining is very easy and is able to be carried out in almost all hospitals; also the TIL count should be reproducible, accurate, and objective . The TIL count can assess preoperatively from biopsy specimens, and can used to decide the treatment strategy.…”

Section: Discussionmentioning

confidence: 99%

Survival impact of lymphocyte infiltration into the tumor of hepatocellular carcinoma in hepatitis B virus‐positive or non‐B non‐C patients who underwent curative resection

Nakagawa

Umezaki

Yamao

et al. 2017

Hepatology Research

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Aim:The prognostic value of lymphocyte infiltration into hepatocellular carcinoma (HCC) is still controversial, and it has not been reported in hepatitis B virus (HBV)-positive or non-B non-C (NBNC) HCC. The aim of this study is to assess the prognostic significance of lymphocyte infiltrate in tumor for HBV-positive and NBNC HCC patients. Results: In patients with low lymphocyte infiltration, the 5-year recurrence rate was higher and OS was poor (86.4 and 44.1%, respectively) than that of the patients with high lymphocyte infiltration (55.3 and 83.7%, respectively). Multivariate analyses revealed that independent risk factors for recurrence were low albumin value (hazard ratio [HR] 2.33, P = 0.009), high American Joint Committee on Cancer (AJCC) T stage (HR 2.31, P < 0.0001), high α-fetoprotein (AFP) value (HR 2.06, P = 0.005), and low lymphocyte infiltration (HR 2.50, P = 0.0001). The independent risk factors for OS were low albumin value (HR 3.69, P = 0.003), high AJCC T stage (HR 2.10, P = 0.049), high AFP value (HR 3.98, P < 0.001), and low lymphocyte infiltration (HR 3.47, P = 0.001).Conclusions: Lymphocyte infiltrate in tumor is significantly associated high recurrence rate and poor overall survival. Evaluation of the infiltrating lymphocyte could improve the prediction of prognosis in HCC patients after curative resection.

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“…By ligation of LIGHT, HVEM stimulates T-cell responses, while binding to BTLA or CD160 leads to inhibition of T-cells. HVEM is known to be expressed in melanoma 29 and most recently in HCC 30 . IDO is the rate-limiting enzyme in the catabolism of the essential amino-acid tryptophan 31 .…”

Section: Introductionmentioning

confidence: 99%

PD-L1, Galectin-9 and CD8⁺ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma

et al. 2017

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Novel systemic treatments for hepatocellular carcinoma (HCC) are strongly needed. Immunotherapy is a promising strategy that can induce specific antitumor immune responses. Understanding the mechanisms of immune resistance by HCC is crucial for development of suitable immunotherapeutics. We used immunohistochemistry on tissue-microarrays to examine the co-expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM and IDO, as well as tumor CD8+ lymphocyte infiltration in HCC, in two independent cohorts of patients. We found that at least some expression in tumor cells was seen in 97% of cases for HVEM, 83% for PD-L1, 79% for Gal-9 and 66% for IDO. In the discovery cohort (n = 94), we found that lack of, or low, tumor expression of PD-L1 (p < 0.001), Galectin-9 (p < 0.001) and HVEM (p < 0.001), and low CD8+TIL count (p = 0.016), were associated with poor HCC-specific survival. PD-L1, Galectin-9 and CD8+TIL count were predictive of HCC-specific survival independent of baseline clinicopathologic characteristics and the combination of these markers was a powerful predictor of HCC-specific survival (HR 0.29; p <0.001). These results were confirmed in the validation cohort (n = 60). We show that low expression levels of PD-L1 and Gal-9 in combination with low CD8+TIL count predict extremely poor HCC-specific survival and it requires a change in two of these parameters to significantly improve prognosis. In conclusion, intra-tumoral expression of these immune inhibiting molecules was observed in the majority of HCC patients. Low expression of PD-L1 and Galectin-9 and low CD8+TIL count are associated with poor HCC-specific survival. Combining immune biomarkers leads to superior predictors of HCC mortality.

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Clinical impact of herpesvirus entry mediator expression in human hepatocellular carcinoma

Abstract: Tumour-expressing HVEM plays a critical role in human HCC, possibly through regulating immune evasion. Therefore, targeting HVEM may be a novel promising therapeutic strategy for HCC.

Cited by 53 publications

References 40 publications

Immune Checkpoint Axes Are Dysregulated in Patients With Alcoholic Hepatitis

Immune Checkpoint Axes Are Dysregulated in Patients With Alcoholic Hepatitis

Survival impact of lymphocyte infiltration into the tumor of hepatocellular carcinoma in hepatitis B virus‐positive or non‐B non‐C patients who underwent curative resection

PD-L1, Galectin-9 and CD8⁺ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma

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Clinical impact of herpesvirus entry mediator expression in human hepatocellular carcinoma

Abstract: Tumour-expressing HVEM plays a critical role in human HCC, possibly through regulating immune evasion. Therefore, targeting HVEM may be a novel promising therapeutic strategy for HCC.

Cited by 53 publications

References 40 publications

Immune Checkpoint Axes Are Dysregulated in Patients With Alcoholic Hepatitis

Immune Checkpoint Axes Are Dysregulated in Patients With Alcoholic Hepatitis

Survival impact of lymphocyte infiltration into the tumor of hepatocellular carcinoma in hepatitis B virus‐positive or non‐B non‐C patients who underwent curative resection

PD-L1, Galectin-9 and CD8+ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma

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Product

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PD-L1, Galectin-9 and CD8⁺ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma