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Deubiquitinases as pivotal regulators of T cell functions

null

《医学前沿（英文）》 2018年 第12卷 第4期   页码 451-462 doi: 10.1007/s11684-018-0651-y

摘要：

T cells efficiently respond to foreign antigens to mediate immune responses against infections but are tolerant to self-tissues. Defect in T cell activation is associated with severe immune deficiencies, whereas aberrant T cell activation contributes to the pathogenesis of diverse autoimmune and inflammatory diseases. An emerging mechanism that regulates T cell activation and tolerance is ubiquitination, a reversible process of protein modification that is counter-regulated by ubiquitinating enzymes and deubiquitinases (DUBs). DUBs are isopeptidases that cleave polyubiquitin chains and remove ubiquitin from target proteins, thereby controlling the magnitude and duration of ubiquitin signaling. It is now well recognized that DUBs are crucial regulators of T cell responses and serve as potential therapeutic targets for manipulating immune responses in the treatment of immunological disorders and cancer. This review will discuss the recent progresses regarding the functions of DUBs in T cells.

关键词： deubiquitinase     ubiquitination     T cell activation     T cell differentiation     T cell tolerance    

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TiO supported IrO for anode reversal tolerance in proton exchange membrane fuel cell

《能源前沿（英文）》 2022年 第16卷 第5期   页码 852-861 doi: 10.1007/s11708-021-0811-7

摘要： Fuel starvation can occur and cause damage to the cell when proton exchange membrane fuel cells operate under complex working conditions. In this case, carbon corrosion occurs. Oxygen evolution reaction (OER) catalysts can alleviate carbon corrosion by introducing water electrolysis at a lower potential at the anode in fuel shortage. The mixture of hydrogen oxidation reaction (HOR) and unsupported OER catalyst not only reduces the electrolysis efficiency, but also influences the initial performance of the fuel cell. Herein, Ti4O7 supported IrOx is synthesized by utilizing the surfactant-assistant method and serves as reversal tolerant components in the anode. When the cell reverse time is less than 100 min, the cell voltage of the MEA added with IrOx/Ti4O7 has almost no attenuation. Besides, the MEA has a longer reversal time (530 min) than IrOx (75 min), showing an excellent reversal tolerance. The results of electron microscopy spectroscopy show that IrOx particles have a good dispersity on the surface of Ti4O7 and IrOx/Ti4O7 particles are uniformly dispersed on the anode catalytic layer. After the stability test, the Ti4O7 support has little decay, demonstrating a high electrochemical stability. IrOx/Ti4O7 with a high dispersity has a great potential to the application on the reversal tolerance anode of the fuel cell.

关键词： proton exchange membrane fuel cell (PEMFC)     fuel starvation     cell reverse     reversal tolerance anode     oxygen evolution reaction    

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CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies

《医学前沿（英文）》 2021年 第15卷 第6期   页码 783-804 doi: 10.1007/s11684-021-0904-z

摘要： The current standard of care in hematological malignancies has brought considerable clinical benefits to patients. However, important bottlenecks still limit optimal achievements following a current medical practice. The genetic complexity of the diseases and the heterogeneity of tumor clones cause difficulty in ensuring long-term efficacy of conventional treatments for most hematological disorders. Consequently, new treatment strategies are necessary to improve clinical outcomes. Chimeric antigen receptor T-cell (CAR T) immunotherapy opens a new path for targeted therapy of hematological malignancies. In this review, through a representative case study, we summarize the current experience of CAR T-cell therapy, the management of common side effects, the causative mechanisms of therapy resistance, and new strategies to improve the efficacy of CAR T-cell therapy.

关键词： CAR T cells     hematological malignancies     review    

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Regulation of T cell immunity by cellular metabolism

null

《医学前沿（英文）》 2018年 第12卷 第4期   页码 463-472 doi: 10.1007/s11684-018-0668-2

摘要：

T cells are an important adaptive immune response arm that mediates cell-mediated immunity. T cell metabolism plays a central role in T cell activation, proliferation, differentiation, and effector function. Specific metabolic programs are tightly controlled to mediate T cell immune responses, and alterations in T cell metabolism may result in many immunological disorders. In this review, we will summarize the main T cell metabolic pathways and the important factors participating in T cell metabolic programming during T cell homeostasis, differentiation, and function.

关键词： T cell immunity     metabolic pathways     nutrient uptake     metabolic checkpoints    

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EBV-associated lymphoproliferative disease post-CAR-T cell therapy

《医学前沿（英文）》 2024年 第18卷 第2期   页码 394-398 doi: 10.1007/s11684-023-1032-8

摘要： Epstein–Barr virus (EBV)-associated lymphoproliferative diseases (EBV-LPDs) are common complications that occur after solid organ transplantation or allogeneic hematopoietic stem-cell transplantation (HSCT). However, their occurrence and treatment post-chimeric antigen receptor-modified T (CAR-T) cell therapy has not been reported. Two patients had been diagnosed with EBV-positive aggressive B-cell lymphoma and experienced relapses after multiple lines of treatment. After receiving CAR-T cell therapy in tandem with autologous HSCT, the patients achieved complete remission. However, with a median time of 38.5 months after CAR-T cell therapy, B-cell-derived EBV-LPDs were diagnosed, and they were relieved through the administration of immune checkpoint inhibitor or B-cell-depleting agents. Collectively, our report suggests that EBV-LPDs may represent a long-term adverse event after CAR-T cell therapy, especially in patients who previously had EBV-positive disorders, and they can be resolved by immune normalization strategy or B-cell depleting therapy.

关键词： EBV-associated lymphoproliferative disease     chimeric antigen receptor T-cell     autologous stem cell transplantation     immune checkpoint inhibitor    

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Chimeric antigen receptor T cell therapies for acute myeloid leukemia

Bin Gu, Jianhong Chu, Depei Wu

《医学前沿（英文）》 2020年 第14卷 第6期   页码 701-710 doi: 10.1007/s11684-020-0763-z

摘要： Abstract Chimeric antigen receptor T cell (CAR T) therapies have achieved unprecedented efficacy in B-cell tumors, prompting scientists and doctors to exploit this strategy to treat other tumor types. Acute myeloid leukemia (AML) is a group of heterogeneous myeloid malignancies. Relapse remains the main cause of treatment failure, especially for patients with intermediate or high risk stratification. Allogeneic hematopoietic stem cell transplantation could be an effective therapy because of the graft-versus-leukemia effect, which unfortunately puts the patient at risk of serious complications, such as graft-versus-host disease. Although the identification of an ideal target antigen for AML is challenging, CAR T therapy remains a highly promising strategy for AML patients, particularly for those who are ineligible to receive a transplantation or have positive minimal residual disease. In this review, we focus on the most recent and promising advances in CAR T therapies for AML.

关键词： acute myeloid leukemia     CAR T     immunotherapy    

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High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells

Synat Kang, Yanyan Li, Yifeng Bao, Yi Li

《医学前沿（英文）》 2019年 第13卷 第1期   页码 69-82 doi: 10.1007/s11684-018-0677-1

摘要：

Cytokine-activated T cells (CATs) can be easily expanded and are widely applied to cancer immunotherapy. However, the good efficacy of CATs is rarely reported in clinical applications because CATs have no or very low antigen specificity. The low-efficacy problem can be resolved using T cell antigen receptor-engineered CAT (TCR-CAT). Herein, we demonstrate that NY-ESO-1157–165 HLA-A*02:01-specific high-affinity TCR (HAT)-transduced CATs can specifically kill cancer cells with good efficacy. With low micromolar range dissociation equilibrium constants, HAT-transduced CATs showed good specificity with no off-target killing. Furthermore, the high-affinity TCR-CATs delivered significantly better activation and cytotoxicity than the equivalent TCR-engineered T cells (TCR-Ts) in terms of interferon-g and granzyme B production and in vitro cancer cell killing ability. TCR-CAT may be a very good alternative to the expensive TCR-T, which is considered an effective personalized cyto-immunotherapy.

关键词： cytokine-activated T cells     high-affinity T cell receptor     cancer immunotherapy     TCR-CAT    

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A giant step forward: chimeric antigen receptor T-cell therapy for lymphoma

Houli Zhao, Yiyun Wang, Elaine Tan Su Yin, Kui Zhao, Yongxian Hu, He Huang

《医学前沿（英文）》 2020年 第14卷 第6期   页码 711-725 doi: 10.1007/s11684-020-0808-3

摘要： The combination of the immunotherapy (i.e., the use of monoclonal antibodies) and the conventional chemotherapy increases the long-term survival of patients with lymphoma. However, for patients with relapsed or treatment-resistant lymphoma, a novel treatment approach is urgently needed. Chimeric antigen receptor T (CAR-T) cells were introduced as a treatment for these patients. Based on recent clinical data, approximately 50% of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy. Moreover, clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy. Other than the CD19-targeted CAR-T, the novel target antigens, such as CD20, CD22, CD30, and CD37, which were greatly expressed on lymphoma cells, were studied under preclinical and clinical evaluations for use in the treatment of lymphoma. Nonetheless, the CAR-T therapy was usually associated with potentially lethal adverse effects, such as the cytokine release syndrome and the neurotoxicity. Therefore, optimizing the structure of CAR, creating new drugs, and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.

关键词： chimeric antigen receptor T (CAR-T) cell     lymphoma     cytokine release syndrome (CRS)     immune effector cell-associated neurotoxicity syndrome (ICANS)    

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Biological features of intrahepatic CD4+CD25+ T cells in the naturally tolerance of rat liver transplantation

LU Ling, ZHANG Feng, PU Liyong, YAO Aihua, YU Yue, SUN Beicheng, LI Guoqiang, WANG Xuehao

《医学前沿（英文）》 2007年 第1卷 第4期   页码 373-376 doi: 10.1007/s11684-007-0072-9

摘要： The biological features of intrahepatic CD4CD25 T regulatory cells in the naturally tolerance of rat liver transplantation were explored. Orthotopic liver transplantation was performed in two allogeneic rat strain combinations, one with fatal immunosuppression despite a complete major histo compatibility complex mismatch. The subjects were divided into three groups according to different donors and recipients [Tolerance group: LEW-to-DA; Rejection group: DA-to-LEW; Syngegnic group (control group): DA-to-DA]. The proportion of intrahepatic CD4CD25 T cells from three groups was determined by flow cytometry (FCM) in different time. The intrahepaitc CD4CD25 T cells were isolated by magnetic activated cell sorting (MACS) method and iden tified by FCM. The Foxp3 mRNA was detected by reverse transcriptase polymerase chain reaction (RT-PCR). And their suppression on the proliferation of CD4CD25 T effector cells was analyzed by cell proliferation assay . Beginning immediately after transplantation, the proportion of Treg cells increased over time in both allogeneic groups but was significantly greater in the Rejection group. The proportion of Treg cells declined after day 5, and such reduction was more dramatic in the Rejection group than in the Tolerance group. Animals in the Tolerance group showed a second increase in the proportion after day 14. Intrahepatic CD4CD25 T cells isolated from spontaneous tolerance models inhibited the proliferation of mixed lymphocyte reaction. The purity of CD4CD25 T cells sorted by MACS was 86%–93%. The CD4CD25 T cells could specifically express the Foxp3 gene compared with CD4CD25 T cells. , the spleen cells from LEW rats can irritate the proliferation of CD4CD25 T cells more obviously than the syngegnic spleen cells. CD4CD25 Tr cells could suppress the proliferation of CD4CD25 T cells, but the inhibition was reversed by exogenous IL-2 (200 U/mL). The CD4CD25 T regulatory cells specifically express the Foxp3 gene, which may play an important role in the induction of liver transplantation tolerance by suppressing the reaction of effective T cells.

关键词： magnetic     LEW-to-DA     effector     MACS     cytometry    

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Phase I study of CBM.CD19 chimeric antigen receptor T cell in the treatment of refractory diffuse largeB-cell lymphoma in Chinese patients

《医学前沿（英文）》 2022年 第16卷 第2期   页码 285-294 doi: 10.1007/s11684-021-0843-8

摘要： Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has shown impressive efficacy in treating B-cell malignancies. A single-center phase I dose-escalation study was conducted to evaluate the safety and efficacy of T cells transduced with CBM.CD19 CAR, a second-generation anti-CD19 CAR bearing 4-1BB costimulatory molecule, for the treatment of patients with refractory diffuse large B-cell lymphoma (DLBCL). Ten heavily treated patients with refractory DLBCL were given CBM.CD19 CAR-T cell (C-CAR011) treatment. The overall response rate was 20% and 50% at 4 and 12 weeks after the infusion of C-CAR011, respectively, and the disease control rate was 60% at 12 weeks after infusion. Treatment-emergent adverse events occurred in all patients. The incidence of cytokine release syndrome in all grades and grade≥3 was 90% and 0, respectively, which is consistent with the safety profile of axicabtagene ciloleucel and tisagenlecleucel. Neurotoxicity or other dose-limiting toxicities was not observed in any dose cohort of C-CAR011 therapy. Antitumor efficacy was apparent across dose cohorts. Therefore, C-CAR011 is a safe and effective therapeutic option for Chinese patients with refractory DLBCL, and further large-scale clinical trials are warranted.

关键词： CAR-T cell therapy     refractory diffuse large B-cell lymphoma     cytokine release syndrome     dose-limiting toxicity    

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Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia

《医学前沿（英文）》 2022年 第16卷 第3期   页码 442-458 doi: 10.1007/s11684-021-0877-y

摘要： T-cell acute lymphoblastic leukemia (T-ALL) is one of the most dangerous hematological malignancies, with high tumor heterogeneity and poor prognosis. More than 60% of T-ALL patients carry NOTCH1 gene mutations, leading to abnormal expression of downstream target genes and aberrant activation of various signaling pathways. We found that chidamide, an HDAC inhibitor, exerts an antitumor effect on T-ALL cell lines and primary cells including an anti-NOTCH1 activity. In particular, chidamide inhibits the NOTCH1-MYC signaling axis by down-regulating the level of the intracellular form of NOTCH1 (NICD1) as well as MYC, partly through their ubiquitination and degradation by the proteasome pathway. We also report here the preliminary results of our clinical trial supporting that a treatment by chidamide reduces minimal residual disease (MRD) in patients and is well tolerated. Our results highlight the effectiveness and safety of chidamide in the treatment of T-ALL patients, including those with NOTCH1 mutations and open the way to a new therapeutic strategy for these patients.

关键词： T-cell acute lymphoblastic leukemia     HDAC inhibitor     chidamide     NOTCH1     MYC     ubiquitination    

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Clinical characteristics and prognostic factors of patients with mature T-cell lymphoid malignancies:

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《医学前沿（英文）》 2015年 第9卷 第4期   页码 468-477 doi: 10.1007/s11684-015-0419-6

摘要：

Mature T-cell lymphoid malignancies comprise a group of heterogeneous diseases that vary in clinicopathological features, biological behavior, treatment response, and prognosis. Bone marrow (BM) infiltration is more commonly present in mature T-cell lymphoid malignancies compared with their B-cell counterparts and hence important for differential diagnosis. In this study, clinical characteristics and prognostic factors were analyzed in 225 patients with mature T-cell lymphoid malignancies treated in a single institution. These included 29 cases of T-cell lymphoproliferative disorders (T-LPD, all with BM infiltration) and 196 cases of T-/natural-killer-cell lymphoma (T/NKCL, 56 with BM infiltration and 140 without BM infiltration). The estimated 5-year overall survival (OS) rates of T-LPD and T/NKCL were 96.6% and 37.3%, respectively. T-LPD patients were less likely to exhibit poor performance status, advanced disease stage, presence of B symptoms, or abnormal level of serum β-2 microglobulin. With similar pathological characteristics, T/NKCL patients with BM infiltration showed significantly lower response rates and shorter OS than those without BM infiltration (P = 0.0264 and P<0.0001, respectively). Multivariate analysis indicated that poor performance status, advanced disease stage, elevated serum lactate dehydrogenase level, and BM involvement were independent unfavorable prognostic factors. The Glasgow Prognostic Score may be more efficient than the International Prognostic Index in predicting disease outcome in T/NKCL. In conclusion, clinical characteristics may be useful in more effectively stratifying patients with mature T-cell lymphoid malignancies.

关键词： mature T-cell lymphoid malignancies     clonal T-cell population     bone marrow infiltration     prognostic factors    

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Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia

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《医学前沿（英文）》 2012年 第6卷 第4期   页码 416-420 doi: 10.1007/s11684-012-0224-4

摘要：

Acute lymphoblastic leukemia includes T-cell acute lymphoblastic leukemia (T-ALL) and B-cell acute lymphoblastic leukemia (B-ALL). In children, T-ALL usually has a worse prognosis than B-ALL, although childhood T-ALL prognoses have improved remarkably. The varying outcomes among T-ALL cases suggest that an unrecognized biological heterogeneity may contribute to chemo-resistance. Deep exploration of T-lymphocyte development in recent years has found a subgroup of patients with a phenotype that resembles early T-cell precursor, which confers a much poorer prognosis than any other form of T-ALL. This novel subtype of T-ALL was called early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Flow cytometry data from T-ALL patients enrolled in Shanghai Children’s Medical Center between July 2002 and October 2010 were assessed according to Dr. Campana’s protocol. Among total 89 T-ALL cases, 74 cases had enough immunophenotype data available to differentiate between ETP (CD1a-, CD8-, CD5dim, at least one marker of stem cell or myeloid lineage) and non-ETP. From these 74 subjects, 12 ETP-ALL cases (16.2%) were identified. The event-free survival (EFS) rate at 66.8 months was 11.1%±10.1% for ETP-ALL and 57.6%±5.6% for non-ETP-ALL (P=0.003). The overall survival rates were 13.3%±11.0% for ETP-ALL and 64.7%±6.3% for non-ETP-ALL (P=0.002). Our findings demonstrate that early T-cell precursor leukemia is a very high-risk subtype of acute lymphoblastic leukemia with poor prognosis.

关键词： acute lymphoblastic leukemia     early T precursor     prognosis    

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Chimeric antigen receptor T-cell therapy: a promising treatment modality for relapsed/refractory mantlecell lymphoma

Ping Li, Ningxin Dong, Yu Zeng, Jie Liu, Xiaochen Tang, Junbang Wang, Wenjun Zhang, Shiguang Ye, Lili Zhou, Alex Hongsheng Chang, Aibin Liang

《医学前沿（英文）》 2020年 第14卷 第6期   页码 811-815 doi: 10.1007/s11684-020-0740-6

摘要： Mantle cell lymphoma (MCL) is a distinct histological type of B-cell lymphoma with a poor prognosis. Several agents, such as proteasome inhibitors, immunomodulatory drugs, and inhibitors of B cell lymphoma-2 and Bruton’s tyrosine kinase have shown efficacy for relapsed or refractory (r/r) MCL but often have short-term responses. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a novel treatment modality for r/r non-Hodgkin’s lymphoma. However, long-term safety and tolerability associated with CAR T-cell therapy are not defined well, especially in MCL. In this report, we described a 70-year-old patient with r/r MCL with 48-month duration of follow-up who achieved long-term remission after CAR T-cell therapy. CAR T-cell-related toxicities were also mild and tolerated well even in this elderly patient. This report suggested that CAR T-cell therapy is a promising treatment modality for patients with MCL, who are generally elderly and have comorbid conditions.

关键词： anti-CD19 chimeric antigen receptor T cells     mantle cell lymphoma     relapsed or refractory     long-term follow-up    

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Natural killer cells in liver diseases

null

《医学前沿（英文）》 2018年 第12卷 第3期   页码 269-279 doi: 10.1007/s11684-018-0621-4

摘要：

The liver has been characterized as a frontline lymphoid organ with complex immunological features such as liver immunity and liver tolerance. Liver tolerance plays an important role in liver diseases including acute inflammation, chronic infection, autoimmune disease, and tumors. The liver contains a large proportion of natural killer (NK) cells, which exhibit heterogeneity in phenotypic and functional characteristics. NK cell activation, well known for its role in the immune surveillance against tumor and pathogen-infected cells, depends on the balance between numerous activating and inhibitory signals. In addition to the innate direct “killer” functions, NK cell activity contributes to regulate innate and adaptive immunity (helper or regulator). Under the setting of liver diseases, NK cells are of great importance for stimulating or inhibiting immune responses, leading to either immune activation or immune tolerance. Here, we focus on the relationship between NK cell biology, such as their phenotypic features and functional diversity, and liver diseases.

关键词： natural killer cell     phenotype     immune activation     immune tolerance     liver diseases    

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标题 作者 时间 类型 操作

Deubiquitinases as pivotal regulators of T cell functions

null

期刊论文

TiO supported IrO for anode reversal tolerance in proton exchange membrane fuel cell

期刊论文

CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies

期刊论文

Regulation of T cell immunity by cellular metabolism

null

期刊论文

EBV-associated lymphoproliferative disease post-CAR-T cell therapy

期刊论文

Chimeric antigen receptor T cell therapies for acute myeloid leukemia

Bin Gu, Jianhong Chu, Depei Wu

期刊论文

High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells

Synat Kang, Yanyan Li, Yifeng Bao, Yi Li

期刊论文

A giant step forward: chimeric antigen receptor T-cell therapy for lymphoma

Houli Zhao, Yiyun Wang, Elaine Tan Su Yin, Kui Zhao, Yongxian Hu, He Huang

期刊论文

Biological features of intrahepatic CD4+CD25+ T cells in the naturally tolerance of rat liver transplantation

LU Ling, ZHANG Feng, PU Liyong, YAO Aihua, YU Yue, SUN Beicheng, LI Guoqiang, WANG Xuehao

期刊论文

Phase I study of CBM.CD19 chimeric antigen receptor T cell in the treatment of refractory diffuse largeB-cell lymphoma in Chinese patients

期刊论文

Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia

期刊论文

Clinical characteristics and prognostic factors of patients with mature T-cell lymphoid malignancies:

null

期刊论文

Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia

null

期刊论文

Chimeric antigen receptor T-cell therapy: a promising treatment modality for relapsed/refractory mantlecell lymphoma

Ping Li, Ningxin Dong, Yu Zeng, Jie Liu, Xiaochen Tang, Junbang Wang, Wenjun Zhang, Shiguang Ye, Lili Zhou, Alex Hongsheng Chang, Aibin Liang

期刊论文

Natural killer cells in liver diseases

null

期刊论文