Science/Hepatology/STTT Academician Tian Zhigang and other teams have made continuous progress in the field of immunology

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iNature patients with chronic hepatitis B (CHB) treated with interferon (IFN)-α usually show poor HBeAg serological responses
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Therefore, there is an unmet need for new therapies for CHB
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On November 5, 2021, Wei Haiming, Tian Zhigang, and Anhui Medical University Li Jiabin from the University of Science and Technology of China published an online communication titled "Restoration of HBV-specific CD8+ T-cell responses by sequential low" in Signal Transduction and Targeted Therapy (IF=18.
19) -dose IL-2 treatment in non-responder patients after IFN-α therapy".
The study included two clinical trials, including 130 CHB patients who had not received treatment; first, 92 patients were receiving Peg-IFN -After α-2b treatment, a systematic analysis of interleukin 2 receptor (IL-2R) expression and inhibitory molecule expression in vitro was performed
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In the second clinical trial, 38 unresponsive patients who failed IFN-α treatment received or did not receive low-dose IL-2 treatment for 24 weeks
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These patients were then examined for hepatitis B virus (HBV) specific CD8+ T cell responses and clinical results
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Although most of the participants who received Peg-IFN-α-2b treatment were non-responders, the study observed a decrease in CD25 expression on their CD4+ T cells, indicating that IFN-α treatment may provide sequential IL-2 treatment A basic principle without the need to increase regulatory T cells (Tregs)
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After sequential treatment with IL-2, the study demonstrated that the number of Tregs and the expression of programmed cell death protein 1 (PD-1) decreased in non-responders
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In addition, continuous IL-2 administration rescued effective immune function, involving the activation of STAT1
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Importantly, IL-2 treatment significantly increases the frequency and function of HBV-specific CD8+ T cells, which translates into improved clinical outcomes in patients with unresponsive CHB, including HBeAg seroconversion
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In summary, the results of the study indicate that sequential IL-2 therapy shows the efficacy of saving the immune function of patients with refractory CHB unresponsiveness
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In addition, on September 15, 2021, Bi Jiacheng, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Tian Zhigang and Sun Haoyu of the University of Science and Technology of China, jointly published an online publication titled "TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity" in Science Advances.
The research paper reported that TIPE2 expression gradually increases during the ontogeny of NK cells, which is related to their maturation stage in mice and humans
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NK-specific TIPE2 deficiency increased mature NK cells in mice.
These TIPE2-deficient NK cells showed enhanced activation, cytotoxicity, and IFN-γ production when stimulated, and enhanced the response to IL-15 maturation
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In addition, TIPE2 inhibited IL-15-triggered mTOR activity in human and murine NK cells
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Therefore, blocking mTOR limits the effect of TIPE2 deficiency on the maturation of IL-15-responsive NK cells
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Finally, NK-specific TIPE2-deficient mice are resistant to tumor growth in vivo
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In summary, the results of this study reveal effective checkpoints for mouse and human NK cell maturation and anti-tumor immunity, indicating a promising method for targeting TIPE2 for NK cell-based immunotherapy (click to read)
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On September 17, 2021, Tian Zhigang and Peng Hui from the University of Science and Technology of China published a research paper entitled "METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells" in Nature Communications.
The research report The expression of m6A "writer" METL3 in tumor-infiltrating NK cells is reduced, and there is a positive correlation between the protein expression level of METL3 and the effector molecules in NK cells
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 The study found that the lack of Mettl3 in NK cells can change the homeostasis of NK cells and inhibit the infiltration and function of NK cells in the tumor microenvironment, leading to accelerated tumor development and shortening the survival period of mice
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The gene encoding SHP-2 has been modified by m6A, and its protein expression is reduced in NK cells deficient in METL3
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Decreased SHP-2 activity makes NK cells slow to respond to IL-15, which is related to the inhibitory activation of AKT and MAPK signaling pathways in METL3-deficient NK cells
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These findings indicate that m6A methylation protects the homeostasis of NK cells and tumor immune surveillance functions (click to read)
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On September 12, 2021, University of Science and Technology of China Peng Hui, Tian Zhigang and Sun Xun jointly published a research paper entitled "Requirement of RORα for Maintenance and Anti-Tumor Immunity of Liver-Resident Natural Killer Cells/ILC1s" in Hepatology Online The study found that RORα is highly expressed in liver-resident NK (LrNK) cells/ILC1s
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LrNK cells/ILC1s in mice subjected to conditional ablation of Rora in LrNK cells/ILC1s and conventional NK (cNK) cells decreased, but the number of cNK cells was normal
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RORα-deficient LrNK cells/ILC1s showed increased apoptosis and significantly altered transcription profiles
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Using a mouse model of colorectal cancer liver metastasis, the study found that RORα conditional defects lead to more radical liver tumor progression and impaired expression of effector molecules in LrNK cells/ILC1
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Therefore, treatment with RORα agonists effectively limits liver metastasis and promotes the expression of effector molecules of LrNK cells/ILC1s
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In summary, this study reveals the previously undefined role of RORα in the maintenance and function of LrNK cells/ILC1, providing insights for the use of LrNK cell/ILC1 activity in the treatment of liver cancer
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On July 6, 2021, Wei Haiming, Tian Zhigang and Sun Zimin of the University of Science and Technology of China jointly published a research paper entitled "Inflammatory monocytes promote pre-engraftment syndrome and tocilizumab can therapeutically limit pathology in patients" in Nature Communications.
The research shows GM-CSF produced by cord blood-derived inflammatory monocytes drives PES pathology, and monocytes are the main source of IL-6 during PES
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In addition, the study reports the results of a single-arm, single-center clinical study of tocilizumab in patients with steroid-refractory severe PES
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The study was in line with the main outcome indicator because there were no non-recurrent deaths during the 100-day follow-up period
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The study also met the key secondary outcome indicators for neutrophil engraftment and hematopoiesis
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These findings provide a treatment strategy to address PES and improve non-relapse mortality (click to read)
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On March 21, 2021, Tian Zhigang, Peng Hui, Sun Yan from the University of Science and Technology of China and Eric Vivier from the University of Marseille in France published a study titled "Liver type 1 innate lymphoid cells develop locally via an interferon-γ-dependent loop" in Science.
The paper, this study found the differentiation potential and regulation mechanism of adult hematopoietic precursor cells into type 1 natural lymphocytes (liver ILC1, that is, liver colonizing NK cells), revealing the new path of natural lymphocytes outside the bone marrow development (click to read)
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Although the 69th World Health Assembly approved a global health sector strategy to eliminate viral hepatitis by 2030, approximately 250 million patients from 120 countries are currently infected with hepatitis B virus (HBV)
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A highly effective treatment for hepatitis C virus (HCV) infection was introduced in 2013, but hepatitis B is to some extent obscured by other public health priorities, and the possibility of a cure is still elusive
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To date, interferon alfa (IFN-α) is the treatment of choice for HBV infection
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IFN-α is thought to activate a series of interferon-stimulating genes (ISG) and degrade nuclear virus DNA (possibly through exosomes or apolipoprotein B editing complex 3 (APOBEC3) DNA editing enzymes)
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In addition, IFN-α enhances the immune function of cytotoxic CD8+ T cells and rescues the cytotoxic activity of natural killer (NK) cells.
Natural killer (NK) cells are an important part of innate antiviral immunity and can quickly respond to viral infections.
Of cells
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The quality and extent of the cytotoxic CD8+ T cell response is important for overcoming chronic viral infections; however, recent studies evaluating the therapeutic effect of IFN-α have reported that the seroconversion rate of hepatitis B e antigen (HBeAg) is only 30%.
Antigen (HBsAg) loss rate is about 5%
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Therefore, during persistent infection, CD8+ T cells alone may not be enough to clear the virus, and NK cells may also be worthy of attention
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Article pattern (picture from Signal Transduction and Targeted Therapy) Although IFN-α can activate T cell response during acute infection, chronic IFN-α exposure may cause immunosuppression and be harmful to T cells that control pathogens
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According to reports, during persistent viral infection, chronic IFN-I signaling may drive immunosuppressive programs, and IFNR blockade significantly improves T cell immunity and control of LCMV infection
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In addition, IFN-α treatment of persistent HBV infection in humans may induce immunomodulatory effects in chronic HBV patients by significantly up-regulating the levels of CD24+CD38hi B cells, which can drive immunosuppressive programs and reduce antiviral effects
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However, in vitro regulation of these inhibitory pathways has only achieved effective functional recovery in a small number of chronic hepatitis B (CHB) patients
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Therefore, the identification of new, well-tolerated therapy for effective treatment of hepatitis B is essential
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Many recent studies have reviewed the various functions of interleukin (IL)-2, such as its antiviral effects by regulating T cells and NK cells, and its role in the treatment of tumors
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IFN-α can increase IL-2 activity and thus play a therapeutic role in CHB
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The combination therapy of IL-2 and IFN-α has shown certain promise in prolonging the survival time of RCC patients
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 However, IL-2 can have serious side effects when administered intravenously and can drive Treg expansion
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CD25 (IL-2Rα) is the "low affinity" form of IL-2 receptor (Kd~ 10-8M)
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CD25-mediated phosphorylation of STAT5) induces FOXP3 expression, which is essential for Treg production
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The pairing of CD122 (IL-2Rβ) and CD132 (IL-2Rγ) subunits results in the formation of a medium-affinity IL-2 receptor (Kd = 10-9M).
When it binds to IL-2, it promotes cytolytic activity and Expansion of T cells
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In addition, the binding of CD25 to medium-affinity receptors leads to the formation of high-affinity receptors (Kd = 10−11M), which are constitutively expressed on CD4+ Tregs at high levels, allowing them to obtain IL-2 with other types of cells
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So far, few studies have shown that IFN-α can inhibit the production of Tregs in peripheral blood mononuclear cells (PBMC) of CHB patients
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This study provides insight into the function of HBV-specific CD8+ T cells during continuous IL-2 treatment
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Here, the study evaluated the expression of immunosuppressive molecules and the percentage of Treg cells in NR patients, and studied the HBV-specific CD8+ T cell response during continuous low-dose IL-2 treatment
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In addition, the study aims to determine whether this approach can improve the clinical outcome of NR patients who have failed initial IFN-α therapy
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