Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion

Sun, Cheng; Lan, Peixiang; Han, Qiuju; Huang, Mei; Xu, Ge‐Liang; Song, Jiuzhou; Wang, Jinyu; Wei, Haiming; Zhang, Jian; Sun, Rui; Zhang, Cai; Tian, Zhigang

doi:10.1038/s41467-018-03584-3

Cited by 75 publications

(63 citation statements)

References 53 publications

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“…The increased serum sPD-L1 levels in chronic HBV infection, especially in the first step from health to infection, are in concordance with the PD-1/PD-L1 axis as a negative immune regulator and HBVinduced the expressions of PD-1 and PD-L1 [9][10][11][12][13][14]. The positive correlation of the serum sPD-L1 with HBsAg further supports the effect of the PD-1/PD-L1 axis on the chronicity of HBV infection.…”

Section: Discussionsupporting

confidence: 64%

“…NUCs lacking of direct effect on viral antigens may be its underlying mechanism to be correlated with the increased serum sPD-L1 since viral antigens or proteins such as HBsAg, HBx protein and viral polymerase up-regulate the PD-L1 expression [14,35].…”

Section: Discussionmentioning

confidence: 99%

“…HBsAg 4 impairs immune response by up-regulation of the PD-L1 expression on monocytes [13]. HBV also promotes the expression of PD-L1 on hepatocytes in cell model and transgenic mice, which correlates with the levels of HBsAg, hepatitis B e antigen (HBeAg) and HBV DNA in mouse sera [14]. The blockage of the PD-1/PD-L1 axis using anti-PD-1 antibody can enhance virus-specific immunity in the woodchuck model of HBV infection [15], and nivolumab therapy is well-tolerated and leads to HBsAg decline in most virally suppressed HBeAg-negative patients (a phase Ib study) [16].…”

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confidence: 99%

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Serum soluble programmed death ligand-1 is correlated with HBsAg level and nucleos(t)ide analogue therapy in chronic hepatitis B

Rm¹,

Wx²,

Lj³

et al. 2020

Preprint

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Background The restoration of immune responses is thought as a complementary approach to the nucleos(t)ide analogue (NUC) therapy of chronic HBV infection. The antiviral immunity is negatively regulated by the programmed cell death-1/programmed death ligand-1 (PD-1/PD-L1) axis. Here, the soluble form of PD-L1 (sPD-L1) that represents the amount of PD-L1 expression cells was used as an indicator to investigate the involvement of this axis in chronic HBV infection, especially in the setting of NUC therapy. Methods A total of 273 adult patients with chronic HBV infection, regardless of the treatment, and 86 healthy controls were consecutively enrolled. Serum sPD-L1 was measured using an ELISA assay. Its correlations with clinical/virological characteristics were analyzed. Results Serum sPD-L1 levels in patients with chronic HBV infection (median 425.2 IQR 245.8-558.6 pg/mL) were significantly higher than those in healthy controls (median 81.69 IQR 54.62-121.1 pg/mL). Among patients at various disease phases, those with immune-tolerant CHB had the lowest sPD-L1 levels (median 205.3 IQR 92.27-340.7 pg/mL). These results indicated that serum sPD-L1 was significantly increased in a manner of two steps from health to infection and from immunotolerance to immunoactivation in chronic HBV infection. Furthermore, the serum sPD-L1 in immune-active CHB was correlated with HBsAg positively, HBV DNA negatively and liver damage marginally. Interestingly, the increased serum sPD-L1 levels were strongly associated with the treatment of NUCs, especially in HBeAg-positive immune-active CHB. Conclusions Serum sPD-L1 might be a meaningful indicator to monitor the immune status and disease progression in chronic HBV infection. The correlations of the increased sPD-L1 with HBsAg and NUC treatment suggest that the activated PD-1/PD-L1 axis may explain the rarity of HBsAg seroconversion of NUC therapy and the clinically available checkpoint inhibitors may serve as partners for NUCs to improve their anti-HBV efficacy in the future

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Serum soluble programmed death ligand-1 is correlated with HBsAg level and nucleos(t)ide analogue therapy in chronic hepatitis B

Rm¹,

Wx²,

Lj³

et al. 2020

Preprint

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“…In agreement with this suggestion, recent studies have shown that SALL4 is a novel sensitive and specific diagnostic marker of ovarian primitive germ cell tumors, hepatoid gastric carcinoma from hepatocellular carcinoma, and testicular germ cell tumors. 7,14,31,32 Therefore, SALL4 oncofetal proteins have great potential to become therapeutic target spots.…”

Section: Discussionmentioning

confidence: 99%

<p>Sal-Like Protein 4 Transcription Factor: A Significant Diagnostic Biomarker Involved in Childhood ALL Resistance and Relapse</p>

Ohadi

Rahgozar

Ghodousi

2020

CMAR

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Purpose: Sal-like protein 4 transcription factor (SALL4) is a stem cell transcription factor that plays an essential role in the maintenance and self-renewal of embryonic and hematopoietic stem cells, functioning as an oncogene in several cancers. However, the role of SALL4 in the biological behavior of childhood acute lymphoblastic leukemia and its relationship with multidrug resistance and relapse has remained largely unknown. Patients and Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to characterize the expression pattern of SALL4 in the bone marrow samples of 43 patients with Philadelphia negative ALL and 18 children in the non-cancer control group. The presence of minimal residual disease was measured a year after the initial therapy using SSCP (single-strand conformation polymorphism). In addition, the correlation between the expression of SALL4 and ABCA3 in relapsed patients was analyzed statistically. Results: Results showed an overexpression of SALL4 in de novo patients compared with the control group (P=0.0001, AUC= 0.93), indicating the importance of this gene in the induction of leukemia. A significant increase in the ABCA3 expression levels was revealed in the relapsed patients, in comparison with the drug-sensitive group (P = 0.0005). The leukemogenetic effect of SALL4 can be related to the effect of this gene on the maintenance of pluripotency in cancer stem cells. Results also suggest that the expression of SALL4 can be considered as a diagnostic marker for pediatric ALL. Moreover, SALL4 expression levels in the minimal residual disease positive (mrd+) ALL group was significantly higher than those in the mrd− group (p=0.0001, AUC= 0.92). Conclusion: These data demonstrate the prognostic impact of SALL4 in childhood ALL. Our findings also indicated a direct correlation between the mRNA expression levels of SALL4 and ABCA3 transporter in the relapsed group of ALL patients (r=0.7). These results describe a possible mechanism by which SALL4 may lead to the development of multidrug resistance.

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“…Viral infections do not always enhance PD-L1 expression, because similar PD-L1 levels are detected in individuals not infected with viruses [61][62][63][64]. Increased PD-L1 levels are related to specific viruses, such as the following: Epstein-Barr virus (EBV) [65][66][67][68], hepatitis B virus (HBV) [69][70][71], hepatitis C virus (HCV) [72][73][74][75], human immunodeficiency virus (HIV) [63,[76][77][78][79], human papilloma virus (HPV) [68,[80][81][82][83], Merkel cell polyomavirus (MCPyV) [84], bovine leukemia virus (BLV) [85], and Kaposi sarcoma-associated herpes virus (KSHV) [86]. The pathobiological mechanisms by which viruses trigger the expression of PD-L1 have been elucidated.…”

Section: Patients With Infectious Diseasesmentioning

confidence: 99%

Humanized Mice as an Effective Evaluation System for Peptide Vaccines and Immune Checkpoint Inhibitors

Kametani

Ohno

Ohshima

et al. 2019

IJMS

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Peptide vaccination was developed for the prevention and therapy of acute and chronic infectious diseases and cancer. However, vaccine development is challenging, because the patient immune system requires the appropriate human leukocyte antigen (HLA) recognition with the peptide. Moreover, antigens sometimes induce a low response, even if the peptide is presented by antigen-presenting cells and T cells recognize it. This is because the patient immunity is dampened or restricted by environmental factors. Even if the immune system responds appropriately, newly-developed immune checkpoint inhibitors (ICIs), which are used to increase the immune response against cancer, make the immune environment more complex. The ICIs may activate T cells, although the ratio of responsive patients is not high. However, the vaccine may induce some immune adverse effects in the presence of ICIs. Therefore, a system is needed to predict such risks. Humanized mouse systems possessing human immune cells have been developed to examine human immunity in vivo. One of the systems which uses transplanted human peripheral blood mononuclear cells (PBMCs) may become a new diagnosis strategy. Various humanized mouse systems are being developed and will become good tools for the prediction of antibody response and immune adverse effects.

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Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion

Cited by 75 publications

References 53 publications

Serum soluble programmed death ligand-1 is correlated with HBsAg level and nucleos(t)ide analogue therapy in chronic hepatitis B

Serum soluble programmed death ligand-1 is correlated with HBsAg level and nucleos(t)ide analogue therapy in chronic hepatitis B

<p>Sal-Like Protein 4 Transcription Factor: A Significant Diagnostic Biomarker Involved in Childhood ALL Resistance and Relapse</p>

Humanized Mice as an Effective Evaluation System for Peptide Vaccines and Immune Checkpoint Inhibitors

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