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Deubiquitinases as pivotal regulators of T cell functions

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《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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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

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《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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Cannabidiol prevents depressive-like behaviors through the modulation of neural stem cell differentiation

《医学前沿（英文）》 2022年第16卷第2期页码 227-239 doi: 10.1007/s11684-021-0896-8

摘要： Chronic stress impairs radial neural stem cell (rNSC) differentiation and adult hippocampal neurogenesis (AHN), whereas promoting AHN can increase stress resilience against depression. Therefore, investigating the mechanism of neural differentiation and AHN is of great importance for developing antidepressant drugs. The nonpsychoactive phytocannabinoid cannabidiol (CBD) has been shown to be effective against depression. However, whether CBD can modulate rNSC differentiation and hippocampal neurogenesis is unknown. Here, by using the chronic restraint stress (CRS) mouse model, we showed that hippocampal rNSCs mostly differentiated into astrocytes under stress conditions. Moreover, transcriptome analysis revealed that the FoxO signaling pathway was involved in the regulation of this process. The administration of CBD rescued depressive-like symptoms in CRS mice and prevented rNSCs overactivation and differentiation into astrocyte, which was partly mediated by the modulation of the FoxO signaling pathway. These results revealed a previously unknown neural mechanism for neural differentiation and AHN in depression and provided mechanistic insights into the antidepressive effects of CBD.

关键词： cannabidiol depression radial neural stem cells neurogenesis

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Stem cell research in hepatocellular carcinoma

SUN Chengyi, ZUO Shi

《医学前沿（英文）》 2008年第2卷第1期页码 1-4 doi: 10.1007/s11684-008-0001-6

摘要： The traditional view that adult human liver tumors, mainly hepatocellular carcinoma (HCC), arise from mature cell types has been challenged in recent decades. The results of several studies suggest that HCC can be derived from liver stem cells. There are four levels of cells in the liver stem cell lineage: hepatocytes, hepatic stem cells/oval cells, bone marrow stem cells and hepato-pancreas stem cells. However, whether HCC is resulted from the differentiation block of stem cells and, moreover, which liver stem cell lineage is the source cell of hepatocarcinogenesis remain controversial. In this review, we focus on the current status of liver stem cell research and their roles in carcinogenesis of HCC, in order to explore new approaches for stem cell therapy of HCC.

关键词： lineage hepato-pancreas differentiation block carcinogenesis current status

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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-1_157–165 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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Repression of CDKN2C caused by PML/RARα binding promotes the proliferation and differentiation block

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《医学前沿（英文）》 2016年第10卷第4期页码 420-429 doi: 10.1007/s11684-016-0478-3

摘要：

Inappropriate cell proliferation during oncogenesis is often accompanied by inactivation of components involved in the cell cycle machinery. Here, we report that cyclin-dependent kinase inhibitor 2C (CDKN2C) as a member of the cyclin-dependent kinase inhibitors is a target of the PML/RARα oncofusion protein in leukemogenesis of acute promyelocytic leukemia (APL). We found that CDKN2C was markedly downregulated in APL blasts compared with normal promyelocytes. Chromatin immunoprecipitation combined with quantitative polymerase chain reaction demonstrated that PML/RARα directly bound to the CDKN2C promoter in the APL patient-derived cell line NB4. Luciferase assays indicated that PML/RARα inhibited the CDKN2C promoter activity in a dose-dependent manner. Furthermore, all-trans retinoic acid treatment induced CDKN2C expression by releasing the PML/RARα binding on chromatin in NB4 cells. Functional studies showed that ectopic expression of CDKN2C induced a cell cycle arrest at the G₀/G₁ phase and a partial differentiation in NB4 cells. Finally, the transcriptional regulation of CDKN2C was validated in primary APL patient samples. Collectively, this study highlights the importance of CDKN2C inactivation in the abnormal cell cycle progression and differentiation block of APL cells and may provide new insights into the study of pathogenesis and targeted therapy of APL.

关键词： CDKN2C acute promyelocytic leukemia cell cycle arrest differentiation

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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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Nano thermo-hydrodynamics method for investigating cell membrane fluidity

YANG Yang, LIU Jing

《能源前沿（英文）》 2008年第2卷第2期页码 121-128 doi: 10.1007/s11708-008-0033-2

摘要： As a barrier to compartmentalize cells, membranes form the interface between a cell and its surroundings. The essential function of a membrane is to maintain a relatively stable environment in the cell, exchange substances selectively and transfer energy and information continually from the outside. It is intriguing that above the phase transition temperature, the membrane lipid molecule will have three modes–lateral diffusion, rotational movement and flip-flop activity. These thermodynamic processes are vital to cell existence, growth, division, differentiation and are also responsible for hundreds of thousands of phenomena in life. Previously, species transport across the membrane was interpreted mainly from a phenomenological view using a lumped system model. Therefore, detailed flow processes occurred in the membrane domain and clues related to life mechanism were not sufficiently tackled. Such important issues can be clarified by modeling nano scale thermal hydrodynamics over the gap space of a cell membrane. Previously observed complex membrane behaviors will be shown in this paper and explained by the thermally induced fluidic convections inside the membrane. A correlation between nano scale hydrodynamics, non-equilibrium thermodynamics and cell membrane activities is set up. The disclosed mechanisms are expected to provide a new viewpoint on the interaction between intracellular and extracellular processes through the membrane.

关键词： responsible phenomenological phenomena modes–lateral diffusion differentiation

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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^-, CD5^dim, 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