Herpes simplex viruses （HSV-1 and HSV-2） cause global morbidity and synergistically correlate with HIV infection. HSV exists life-long in a latent form in sensory neurons with intermittent reactivation, in despite o...Herpes simplex viruses （HSV-1 and HSV-2） cause global morbidity and synergistically correlate with HIV infection. HSV exists life-long in a latent form in sensory neurons with intermittent reactivation, in despite of host immune surveillatlce. While abundant evidence for HSV interfering with innate immune responses so as to favor the replication and propagation of the virus, several lines of evidence declare that HSV attenuates adaptive immunity by various mechanisms, including but not limited to the ablation of antigen presentation, induction of apoptosis, and interruption of cellular signaling. In this review, we will focus on the perturbative role of HSV in T cells signaling.展开更多
Novel aspects of T cells containing TCRVβ20-1 are numerous, ranging from pathogen specific reactivity to specific tissue homing, or possible T cell subsets. Recently, it was demonstrated that TCR itself could become ...Novel aspects of T cells containing TCRVβ20-1 are numerous, ranging from pathogen specific reactivity to specific tissue homing, or possible T cell subsets. Recently, it was demonstrated that TCR itself could become reactive by binding to small molecules free of the pHLA interface. Our work here was to identify a natural ligand binding to an identified pocket on the CDR2β loop of these TCR. Using docking of suspected ligands, we were able to show Guanine and Adenine diand tri-nucleotides readily bind to the identified site. Comparing these with small molecule sites found on other TCR types, we show this interaction is novel. With further molecular dynamic simulations, these sites are shown to be plausible by conducting simple computational based solubility tests as cross validation. Combined with simple proliferative responses, the identified nucleotides are also shown to have functional consequences by inducing T cell proliferation for CD4/Vβ20-1 + T cells, while failing to induce proliferation in other T cell isolates. Merging computational and simple cell assays, this work establishes a role of nucleotides in T cells found to contain this TCR subtype.展开更多
Objectives:The Kirsten rat sarcoma virus(KRAS)G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions.This study aims to explore...Objectives:The Kirsten rat sarcoma virus(KRAS)G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions.This study aims to explore innovative approaches in T cell receptor(TCR)engineering and characterization to target the KRAS G12D7-16 mutation,providing potential strategies for overcoming this therapeutic challenge.Methods:In this innovative study,we engineered and characterized two T cell receptors(TCRs),KDA11-01 and KDA11-02 with high affinity for the KRAS G12D7-16 mutation.These TCRs were isolated from tumor-infiltrating lymphocytes(TILs)derived from tumor tissues of patients with the KRAS G12D mutation.We assessed their specificity and anti-tumor activity in vitro using various cancer cell lines.Results:KDA11-01 and KDA11-02 demonstrated exceptional specificity for the HLA-A*11:01-restricted KRAS G12D7-16 epitope,significantly inducing IFN-γrelease and eliminating tumor cells without cross-reactivity or alloreactivity.Conclusions:The successful development of KDA11-01 and KDA11-02 introduces a novel and precise TCR-based therapeutic strategy against KRAS G12D mutation,showing potential for significant advancements in cancer immunotherapy.展开更多
Objectives To explore the pathogenesis of rheumatoid arthritis (RA) by studying the expression of T cell receptors (TCRs).Methods T cell receptor Vβ (TCR Vβ) gene usage and expression were analyzed from synovial mem...Objectives To explore the pathogenesis of rheumatoid arthritis (RA) by studying the expression of T cell receptors (TCRs).Methods T cell receptor Vβ (TCR Vβ) gene usage and expression were analyzed from synovial membrane and peripheral blood of 8 RA patients, 2 osteoarthritis patients and 2 accident amputees. The complementary determining region 3 (CDR3) of 25 TCR Vβ subfamily genes in unselected T cell populations were amplified semi-quantitatively by reverse transcription-polymerase chain reaction (RT-PCR). The products were further studied by genescan for frequency of Vβ usage.Results The numbers of Vβ subfamilies expressed by T cells from RA peripheral blood and synovial membrane were not significantly restricted. More importantly, biased Vβ gene expression in RA synovium was observed and Vβ6, Vβ17, and Vβ22 genes were the predominant subfamilies. It was noteworthy that the expression of Vβ17 in RA synovium was significantly increased. Conclusion Our data were consistent with the hypothesis that several antigen or superantigen-driven processes may be involved in the pathogenesis of RA.展开更多
γδ T cells form an important part of adaptive immune responses against infections and malignant transformation. The molecular targets of humanγδT cell receptors （TCRs） remain largely unknown, but recent studies ...γδ T cells form an important part of adaptive immune responses against infections and malignant transformation. The molecular targets of humanγδT cell receptors （TCRs） remain largely unknown, but recent studies have confirmed the recognition of phosphorylated prenyl metabolites, lipids in complex with CD1 molecules and markers of cellular stress. All of these molecules are upregulated on various cancer types, highlighting the potential importance of the γδ T cell compartment in cancer immunosurveiliance and paving the way for the use of γδTCRs in cancer therapy. Ligand recognition by the γδ TCR often requires accessorylco-stimulatory stress molecules on both T cells and target cells; this cellular stress context therefore provides a failsafe against harmful self-reactivity. Unlike αβ T cells, γδ T cells recognise their targets irrespective of HLA haplotype and therefore offer exciting possibilities for off-the-shelf, pan-population cancer immunotherapies. Here, we present a review of known ligands of human γδ T cells and discuss the promise of harnessing these cells for cancer treatment.展开更多
Background Recent studies have suggested that mature T cells can change their specificity through reexpression of recombination-activating genes （RAG） and RAG-mediated V（D）J recombination. This process is named re...Background Recent studies have suggested that mature T cells can change their specificity through reexpression of recombination-activating genes （RAG） and RAG-mediated V（D）J recombination. This process is named receptor revision and has been observed in mature peripheral T cells from transgenic mice and human donors. However, whether the receptor revision in mature T cells is a random or orientated process remains poorly understood. Here we used the Jurkat human T cell line, which represents a mature stage of T cell development, as a model to investigate the regulation of T cell receptor （TCR） gene recombination. Methods TCR Dβ-Jβ signal joint T cell receptor excision DNA circles （sjTRECs） were determined by nested and seminested PCR. Double-strand DNA breaks at recombination signal sequences （RSSs） in the TCRVβ chain locus were detected by ligation-mediated-PCR. Further analysis of the complementarity-determining region 3 （CDR3） size of the TCRVβ chain was examined by the TCR GeneScan technique. Results RAG1, RAG2, and three crucial components of the nonhomologous DNA end-joining （NHEJ） pathway were readily detected in Jurkat. Characteristics of junctional diversity of Dβ2-Jβ2 signal joints and ds RSS breaks associated with the Dβ2 5＇ and Dβ 2 3＇ sites were detected in DNA from Jurkat cells. CDR3 size and the gene sequences of the TCRVβ chain did not change during cell proliferation. Conclusions RAG1 and RAG2 and ongoing TCR gene recombination are coexpressed in Jurkat cells, but the ongoing recombination process may not play a role in modification of the TCR repertoire.However, the results suggest that Jurkat could be used as a model for studying the regulation of RAGs and V（D）J recombination and as a ＂special＂ model of the coexistence of TCR gene rearrangements and ＂negative＂ receptor revision.展开更多
Gastric cancer,a prevalent malignancy worldwide,ranks sixth in terms of frequency and third in fatality,causing over a million new cases and 769000 annual deaths.Predominant in Eastern Europe and Eastern Asia,risk fac...Gastric cancer,a prevalent malignancy worldwide,ranks sixth in terms of frequency and third in fatality,causing over a million new cases and 769000 annual deaths.Predominant in Eastern Europe and Eastern Asia,risk factors include family medical history,dietary habits,tobacco use,Helicobacter pylori,and Epstein-Barr virus infections.Unfortunately,gastric cancer is often diagnosed at an advanced stage,leading to a grim prognosis,with a 5-year overall survival rate below 5%.Surgical intervention,particularly with D2 Lymphadenectomy,is the mainstay for early-stage cases but offers limited success.For advanced cases,the National Comprehensive Cancer Network recommends chemotherapy,radiation,and targeted therapy.Emerging immunotherapy presents promise,especially for unresectable or metastatic cases,with strategies like immune checkpoint inhibitors,tumor vaccines,adoptive immunotherapy,and nonspecific immunomodulators.In this Editorial,with regards to the article“Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review”,we address the advances in the field of immunotherapy in gastric cancer and its future prospects.展开更多
The diversity of antigen receptors and the specificity it underlies are the hallmarks of the cellular arm of the adaptive immune system. T and B lymphocytes are indeed truly unique in their ability to generate recepto...The diversity of antigen receptors and the specificity it underlies are the hallmarks of the cellular arm of the adaptive immune system. T and B lymphocytes are indeed truly unique in their ability to generate receptors capable of recognizing virtually any pathogen. It has been known for several decades that T lymphocytes recognize short peptides derived from degraded proteins presented by major histocompatibility complex （MHC） molecules at the cell surface. Interaction between peptide-MHC （pMHC） and the T cell receptor （TCR） is central to both thymic selection and peripheral antigen recognition. It is widely assumed that TCR diversity is required, or at least highly desirable, to provide sufficient immune coverage. However, a number of immune responses are associated with the selection of predictable, narrow, or skewed repertoires and public TCR chains. Here, we summarize the current knowledge on the formation of the TCR repertoire and its maintenance in health and disease. We also outline the various molecular mechanisms that govern the composition of the pre-selection, naive and antigen-specific TCR repertoires. Finally, we suggest that with the development of high-throughput sequencing, common TCR ＇signatures＇ raised against specific antigens could provide important diagnostic biomarkers and surrogate predictors of disease onset, progression and outcome.展开更多
The T cell receptor(TCR)is one of the most complicated receptors in mammalian cells,and its triggering mechanism remains mysterious.As an octamer complex,TCR comprises an antigen-binding subunit(TCRαβ)and three CD3 ...The T cell receptor(TCR)is one of the most complicated receptors in mammalian cells,and its triggering mechanism remains mysterious.As an octamer complex,TCR comprises an antigen-binding subunit(TCRαβ)and three CD3 signaling subunits(CD3ζζ,CD3δε,and CD3γε).Engagement of TCRαβwith an antigen peptide presented on the MHC leads to tyrosine phosphorylation of the immunoreceptor tyrosine-based activation motif(ITAM)in CD3 cytoplasmic domains(CDs),thus translating extracellular binding kinetics to intracellular signaling events.Whether conformational change plays an important role in the transmembrane signal transduction of TCR is under debate.Attracted by the complexity and functional importance of TCR,many groups have been studying TCR structure and triggering for decades using diverse biochemical and biophysical tools.Here,we synthesize these structural studies and discuss the relevance of the conformational change model in TCR triggering.展开更多
嵌合抗原受体T细胞(chimeric antigen receptor T cell,CAR-T)成功治疗复发难治性白血病的历史已超过十年,如今,已有多款CAR-T细胞疗法获批用于治疗白血病和淋巴瘤等血液系统癌症,标志着免疫细胞治疗时代的到来。大量研究结果提示,CAR-...嵌合抗原受体T细胞(chimeric antigen receptor T cell,CAR-T)成功治疗复发难治性白血病的历史已超过十年,如今,已有多款CAR-T细胞疗法获批用于治疗白血病和淋巴瘤等血液系统癌症,标志着免疫细胞治疗时代的到来。大量研究结果提示,CAR-T细胞疗法在实体瘤治疗领域同样充满潜力,但相关临床研究数据却不令人满意。CAR-T细胞疗法在实体瘤中面临靶抗原特异性不足、肿瘤物理屏障、异常代谢及免疫抑制性肿瘤微环境等多重不利因素,需要继续深入相关机制的研究,借助基因工程技术对CAR-T细胞进行改造,进一步提升其对实体瘤的疗效。本文就近年来CAR-T细胞疗法在实体瘤中的研究进展做一述评,探讨未来CAR-T细胞治疗的挑战和发展方向。展开更多
The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2(MDM2,also termed HDM2 in humans)through a feedback mechanism.At...The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2(MDM2,also termed HDM2 in humans)through a feedback mechanism.At the same time,TP53 is the most frequently mutated gene in human cancers.Mutant p53 proteins lose wild-type p53 tumor suppression functions but acquire new oncogenic properties,among which are deregulating cell proliferation,increasing chemoresistance,disrupting tissue architecture,and promoting migration,invasion and metastasis as well as several other pro-oncogenic activities.The oncogenic p53 mutation Y220C creates an extended surface crevice in the DNA-binding domain destabilizing p53 and causing its denaturation and aggregation.This cavity accommodates stabilizing small molecules that have therapeutic values.The development of suitable small-molecule stabilizers is one of the therapeutic strategies for reactivating the Y220C mutant protein.In this review,we summarize approaches that target p53-Y220C,including reactivating this mutation with small molecules that bind Y220C to the hydrophobic pocket and developing immunotherapies as the goal for the near future,which target tumor cells that express the p53-Y220C neoantigen.展开更多
Objective: To analyze the distribution and clonality of TCR Vβ subfamily T cells in hairy cell leukemia (HCL) and common-acute lymphoblastic leukemia (c-ALL). Methods: Peripheral blood mononuclear cell samples from 3...Objective: To analyze the distribution and clonality of TCR Vβ subfamily T cells in hairy cell leukemia (HCL) and common-acute lymphoblastic leukemia (c-ALL). Methods: Peripheral blood mononuclear cell samples from 3 cases of HCL and 1 case of c-ALL were investigated for analysis of complementarity determining region 3 (CDR3) size of T cell receptor Vβ repertoire using reverse transcriptase-polymerase chain reaction (RT-PCR). The products were further analyzed by genescan to identify T cell clonality. Results: Some Vβ subfamily PCR products from 4 patients contained monopeak (monoclone) or a dominant peak (oligoclone). In contrast, multipeak (polyclone) distributions were found in all Vβ subfamily PCR products from normal control cases. Conclusion: T cell clonal expansion may be found in HCL and c-ALL cases that may indicate a host response directed against leukemia related antigen. In addition, it may be useful to detect the minimal residual disease.展开更多
The immunophenotype, rearrangements of T cell receptor(TCR) γ andδchain genes as well as the immunoglobulinheavy chain (IgH)gene were studied in 37 cases ofmorphologically defined acute lymphoblastic leukemi...The immunophenotype, rearrangements of T cell receptor(TCR) γ andδchain genes as well as the immunoglobulinheavy chain (IgH)gene were studied in 37 cases ofmorphologically defined acute lymphoblastic leukemia (ALL).According to the expression of differentiation antigens, 8 caseswere classified as T-ALL, 26 B lineage ALL, 2 acute un-differentiated leukemia (AUL) and myeloid phenotype. An or-der of TCR gene rearrangements was observed in T-ALL,with the rearrangement of δgene preceding that of γgene.Both genes were also found frequently rearranged and / or de-leted in high proportions of the ALL of B cell lineage. Howev-er, the patterns of gene rearrangements were somewhat differ-ent between the T and B lineage ALLs. In contrast, the lgHgene rearrangements were observed only in the B lineage ALL.The immunogenotype analysis of ALL proved to be a usefulmarker of the clonality and provided us with important informa-tion on early human lymphoid differentiation. We concludethat the determination of T展开更多
Background Tumors with different gene expression develop and progress in different ways. To deepen our understanding of the progression in endometrial cancer, and provide a useful tool for accurate diagnosis and progn...Background Tumors with different gene expression develop and progress in different ways. To deepen our understanding of the progression in endometrial cancer, and provide a useful tool for accurate diagnosis and prognosis assessment, we identified the new molecular prognostic markers in endometrial carcinoma and analyzed the relationship of them with clinical and pathological features of endometrial carcinoma. Methods Ninety-four cases of endometrial endometrioid adenocarcinoma with complete data from the Peking University People＇s Hospital from 2000 to 2008 and 40 cases of normal endometrium were enrolled. Among these, 30 endometrial endometrioid adenocarcinoma samples of different International Federation of Gynecology and Obstetrics （FIGO） stage were selected for further Agilent genome-wide microarray analysis. Significance analysis of microarrays （SAM） was used to identify genes that are significantly associated with tumor progress. Immunohistochemistry was utilized to identify the genes of interest in endometrial carcinoma and normal endometrium. The relationship between the genes and the age, clinical stage, histological grade, myometrium invaded depth, lymph node metastasis status, and the expression of ER, PR, P53, and PTEN were analyzed by X2 test. Results Analysis between FIGO 1988 stage I and stage III identified a 362-gene ＂progress signature＂; 171 downregulated and 191 up-regulated genes. Among the alterative genes, TARP （T cell receptor gamma alternate reading frame protein） and KRT5 （keratin 5） decreased 3.57 fold and 5.8 fold in FIGO stage III patients. The expression of TARP in endometrial carcinoma increased compared to normal endometrium, while that of KRT5 decreased （P〈0.05）. The expression of TARP and KRT5 decreased when stage, histological grading, myometrium invaded depth increased （P〈0.05）. In the cases with lymph node metastasis, the expression of TARP decreased, while the expression of KRT5 did not differ （both P〈0.05） both. The expression of P53 had a negative relationship with the expression of KRT5 （P〈0.05）, but not with the expression of TARP （P〉0.05）. There was no correlation between the expression of TARP and KRT5 and the expression of ER, PR, PTEN （all P〉0.05）. There was no significant difference in TARP and KRT5 expression in patients aged 50 or younger and patients older than 50 （P〉0.05）. Conclusion The expression of TARP and KRT5 was correlated with the progress of endometrial cancer and their role needs further study.展开更多
基金National Natural Science Foundation of China (30670080)Ministry of Science and Technology of China (2007CB914800,2006CB910103)
文摘Herpes simplex viruses （HSV-1 and HSV-2） cause global morbidity and synergistically correlate with HIV infection. HSV exists life-long in a latent form in sensory neurons with intermittent reactivation, in despite of host immune surveillatlce. While abundant evidence for HSV interfering with innate immune responses so as to favor the replication and propagation of the virus, several lines of evidence declare that HSV attenuates adaptive immunity by various mechanisms, including but not limited to the ablation of antigen presentation, induction of apoptosis, and interruption of cellular signaling. In this review, we will focus on the perturbative role of HSV in T cells signaling.
文摘Novel aspects of T cells containing TCRVβ20-1 are numerous, ranging from pathogen specific reactivity to specific tissue homing, or possible T cell subsets. Recently, it was demonstrated that TCR itself could become reactive by binding to small molecules free of the pHLA interface. Our work here was to identify a natural ligand binding to an identified pocket on the CDR2β loop of these TCR. Using docking of suspected ligands, we were able to show Guanine and Adenine diand tri-nucleotides readily bind to the identified site. Comparing these with small molecule sites found on other TCR types, we show this interaction is novel. With further molecular dynamic simulations, these sites are shown to be plausible by conducting simple computational based solubility tests as cross validation. Combined with simple proliferative responses, the identified nucleotides are also shown to have functional consequences by inducing T cell proliferation for CD4/Vβ20-1 + T cells, while failing to induce proliferation in other T cell isolates. Merging computational and simple cell assays, this work establishes a role of nucleotides in T cells found to contain this TCR subtype.
基金funded by the key R&D Project of Hubei Province(Social Development),China(2022BCA018)the Cooperative Innovation Center of Industrial Fermentation(Ministry of Education&Hubei Province),China(2022KF16)to Kanghong Hu.
文摘Objectives:The Kirsten rat sarcoma virus(KRAS)G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions.This study aims to explore innovative approaches in T cell receptor(TCR)engineering and characterization to target the KRAS G12D7-16 mutation,providing potential strategies for overcoming this therapeutic challenge.Methods:In this innovative study,we engineered and characterized two T cell receptors(TCRs),KDA11-01 and KDA11-02 with high affinity for the KRAS G12D7-16 mutation.These TCRs were isolated from tumor-infiltrating lymphocytes(TILs)derived from tumor tissues of patients with the KRAS G12D mutation.We assessed their specificity and anti-tumor activity in vitro using various cancer cell lines.Results:KDA11-01 and KDA11-02 demonstrated exceptional specificity for the HLA-A*11:01-restricted KRAS G12D7-16 epitope,significantly inducing IFN-γrelease and eliminating tumor cells without cross-reactivity or alloreactivity.Conclusions:The successful development of KDA11-01 and KDA11-02 introduces a novel and precise TCR-based therapeutic strategy against KRAS G12D mutation,showing potential for significant advancements in cancer immunotherapy.
文摘Objectives To explore the pathogenesis of rheumatoid arthritis (RA) by studying the expression of T cell receptors (TCRs).Methods T cell receptor Vβ (TCR Vβ) gene usage and expression were analyzed from synovial membrane and peripheral blood of 8 RA patients, 2 osteoarthritis patients and 2 accident amputees. The complementary determining region 3 (CDR3) of 25 TCR Vβ subfamily genes in unselected T cell populations were amplified semi-quantitatively by reverse transcription-polymerase chain reaction (RT-PCR). The products were further studied by genescan for frequency of Vβ usage.Results The numbers of Vβ subfamilies expressed by T cells from RA peripheral blood and synovial membrane were not significantly restricted. More importantly, biased Vβ gene expression in RA synovium was observed and Vβ6, Vβ17, and Vβ22 genes were the predominant subfamilies. It was noteworthy that the expression of Vβ17 in RA synovium was significantly increased. Conclusion Our data were consistent with the hypothesis that several antigen or superantigen-driven processes may be involved in the pathogenesis of RA.
文摘γδ T cells form an important part of adaptive immune responses against infections and malignant transformation. The molecular targets of humanγδT cell receptors （TCRs） remain largely unknown, but recent studies have confirmed the recognition of phosphorylated prenyl metabolites, lipids in complex with CD1 molecules and markers of cellular stress. All of these molecules are upregulated on various cancer types, highlighting the potential importance of the γδ T cell compartment in cancer immunosurveiliance and paving the way for the use of γδTCRs in cancer therapy. Ligand recognition by the γδ TCR often requires accessorylco-stimulatory stress molecules on both T cells and target cells; this cellular stress context therefore provides a failsafe against harmful self-reactivity. Unlike αβ T cells, γδ T cells recognise their targets irrespective of HLA haplotype and therefore offer exciting possibilities for off-the-shelf, pan-population cancer immunotherapies. Here, we present a review of known ligands of human γδ T cells and discuss the promise of harnessing these cells for cancer treatment.
基金grants from Major State Basic Research Development 973 Program of China(No.2001CB510008 and 2003CB514113)NSFC & Research Grant Coancil of Hong Kong Joint Research Fund(No.30418003).
文摘Background Recent studies have suggested that mature T cells can change their specificity through reexpression of recombination-activating genes （RAG） and RAG-mediated V（D）J recombination. This process is named receptor revision and has been observed in mature peripheral T cells from transgenic mice and human donors. However, whether the receptor revision in mature T cells is a random or orientated process remains poorly understood. Here we used the Jurkat human T cell line, which represents a mature stage of T cell development, as a model to investigate the regulation of T cell receptor （TCR） gene recombination. Methods TCR Dβ-Jβ signal joint T cell receptor excision DNA circles （sjTRECs） were determined by nested and seminested PCR. Double-strand DNA breaks at recombination signal sequences （RSSs） in the TCRVβ chain locus were detected by ligation-mediated-PCR. Further analysis of the complementarity-determining region 3 （CDR3） size of the TCRVβ chain was examined by the TCR GeneScan technique. Results RAG1, RAG2, and three crucial components of the nonhomologous DNA end-joining （NHEJ） pathway were readily detected in Jurkat. Characteristics of junctional diversity of Dβ2-Jβ2 signal joints and ds RSS breaks associated with the Dβ2 5＇ and Dβ 2 3＇ sites were detected in DNA from Jurkat cells. CDR3 size and the gene sequences of the TCRVβ chain did not change during cell proliferation. Conclusions RAG1 and RAG2 and ongoing TCR gene recombination are coexpressed in Jurkat cells, but the ongoing recombination process may not play a role in modification of the TCR repertoire.However, the results suggest that Jurkat could be used as a model for studying the regulation of RAGs and V（D）J recombination and as a ＂special＂ model of the coexistence of TCR gene rearrangements and ＂negative＂ receptor revision.
文摘Gastric cancer,a prevalent malignancy worldwide,ranks sixth in terms of frequency and third in fatality,causing over a million new cases and 769000 annual deaths.Predominant in Eastern Europe and Eastern Asia,risk factors include family medical history,dietary habits,tobacco use,Helicobacter pylori,and Epstein-Barr virus infections.Unfortunately,gastric cancer is often diagnosed at an advanced stage,leading to a grim prognosis,with a 5-year overall survival rate below 5%.Surgical intervention,particularly with D2 Lymphadenectomy,is the mainstay for early-stage cases but offers limited success.For advanced cases,the National Comprehensive Cancer Network recommends chemotherapy,radiation,and targeted therapy.Emerging immunotherapy presents promise,especially for unresectable or metastatic cases,with strategies like immune checkpoint inhibitors,tumor vaccines,adoptive immunotherapy,and nonspecific immunomodulators.In this Editorial,with regards to the article“Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review”,we address the advances in the field of immunotherapy in gastric cancer and its future prospects.
文摘The diversity of antigen receptors and the specificity it underlies are the hallmarks of the cellular arm of the adaptive immune system. T and B lymphocytes are indeed truly unique in their ability to generate receptors capable of recognizing virtually any pathogen. It has been known for several decades that T lymphocytes recognize short peptides derived from degraded proteins presented by major histocompatibility complex （MHC） molecules at the cell surface. Interaction between peptide-MHC （pMHC） and the T cell receptor （TCR） is central to both thymic selection and peripheral antigen recognition. It is widely assumed that TCR diversity is required, or at least highly desirable, to provide sufficient immune coverage. However, a number of immune responses are associated with the selection of predictable, narrow, or skewed repertoires and public TCR chains. Here, we summarize the current knowledge on the formation of the TCR repertoire and its maintenance in health and disease. We also outline the various molecular mechanisms that govern the composition of the pre-selection, naive and antigen-specific TCR repertoires. Finally, we suggest that with the development of high-throughput sequencing, common TCR ＇signatures＇ raised against specific antigens could provide important diagnostic biomarkers and surrogate predictors of disease onset, progression and outcome.
基金We thank Wei Wu and Chengsong Yan for thoughtful discussions.C.X.is funded by CAS grants(Strategic Priority Research Program XDB29000000Facility-based Open Research Program QYZDB-SSW-SMC048+4 种基金Fountain-Valley Life Sciences Fund of University of Chinese Academy of Sciences Education Foundation)NSFC grant(31861133009,31621003)MOST Grant(2018YFA0800700)the Ten Thousand Talent Program“Leading Talent”of ChinaH.L.is funded by an NSFC grant(31670751).
文摘The T cell receptor(TCR)is one of the most complicated receptors in mammalian cells,and its triggering mechanism remains mysterious.As an octamer complex,TCR comprises an antigen-binding subunit(TCRαβ)and three CD3 signaling subunits(CD3ζζ,CD3δε,and CD3γε).Engagement of TCRαβwith an antigen peptide presented on the MHC leads to tyrosine phosphorylation of the immunoreceptor tyrosine-based activation motif(ITAM)in CD3 cytoplasmic domains(CDs),thus translating extracellular binding kinetics to intracellular signaling events.Whether conformational change plays an important role in the transmembrane signal transduction of TCR is under debate.Attracted by the complexity and functional importance of TCR,many groups have been studying TCR structure and triggering for decades using diverse biochemical and biophysical tools.Here,we synthesize these structural studies and discuss the relevance of the conformational change model in TCR triggering.
文摘嵌合抗原受体T细胞(chimeric antigen receptor T cell,CAR-T)成功治疗复发难治性白血病的历史已超过十年,如今,已有多款CAR-T细胞疗法获批用于治疗白血病和淋巴瘤等血液系统癌症,标志着免疫细胞治疗时代的到来。大量研究结果提示,CAR-T细胞疗法在实体瘤治疗领域同样充满潜力,但相关临床研究数据却不令人满意。CAR-T细胞疗法在实体瘤中面临靶抗原特异性不足、肿瘤物理屏障、异常代谢及免疫抑制性肿瘤微环境等多重不利因素,需要继续深入相关机制的研究,借助基因工程技术对CAR-T细胞进行改造,进一步提升其对实体瘤的疗效。本文就近年来CAR-T细胞疗法在实体瘤中的研究进展做一述评,探讨未来CAR-T细胞治疗的挑战和发展方向。
基金funded by the Ministry of Science and Higher Education of the Russian Federation(Grant No.075-15-2020-795 of 29.09.2020,unique project ID:RF-190220X0027).
文摘The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2(MDM2,also termed HDM2 in humans)through a feedback mechanism.At the same time,TP53 is the most frequently mutated gene in human cancers.Mutant p53 proteins lose wild-type p53 tumor suppression functions but acquire new oncogenic properties,among which are deregulating cell proliferation,increasing chemoresistance,disrupting tissue architecture,and promoting migration,invasion and metastasis as well as several other pro-oncogenic activities.The oncogenic p53 mutation Y220C creates an extended surface crevice in the DNA-binding domain destabilizing p53 and causing its denaturation and aggregation.This cavity accommodates stabilizing small molecules that have therapeutic values.The development of suitable small-molecule stabilizers is one of the therapeutic strategies for reactivating the Y220C mutant protein.In this review,we summarize approaches that target p53-Y220C,including reactivating this mutation with small molecules that bind Y220C to the hydrophobic pocket and developing immunotherapies as the goal for the near future,which target tumor cells that express the p53-Y220C neoantigen.
文摘Objective: To analyze the distribution and clonality of TCR Vβ subfamily T cells in hairy cell leukemia (HCL) and common-acute lymphoblastic leukemia (c-ALL). Methods: Peripheral blood mononuclear cell samples from 3 cases of HCL and 1 case of c-ALL were investigated for analysis of complementarity determining region 3 (CDR3) size of T cell receptor Vβ repertoire using reverse transcriptase-polymerase chain reaction (RT-PCR). The products were further analyzed by genescan to identify T cell clonality. Results: Some Vβ subfamily PCR products from 4 patients contained monopeak (monoclone) or a dominant peak (oligoclone). In contrast, multipeak (polyclone) distributions were found in all Vβ subfamily PCR products from normal control cases. Conclusion: T cell clonal expansion may be found in HCL and c-ALL cases that may indicate a host response directed against leukemia related antigen. In addition, it may be useful to detect the minimal residual disease.
基金This work was supported by grants from the Shanghai Foundation for Natural Sciences,the Ministry of Health,.for Young Researchers and the National Natural Sciences Foundation of China
文摘The immunophenotype, rearrangements of T cell receptor(TCR) γ andδchain genes as well as the immunoglobulinheavy chain (IgH)gene were studied in 37 cases ofmorphologically defined acute lymphoblastic leukemia (ALL).According to the expression of differentiation antigens, 8 caseswere classified as T-ALL, 26 B lineage ALL, 2 acute un-differentiated leukemia (AUL) and myeloid phenotype. An or-der of TCR gene rearrangements was observed in T-ALL,with the rearrangement of δgene preceding that of γgene.Both genes were also found frequently rearranged and / or de-leted in high proportions of the ALL of B cell lineage. Howev-er, the patterns of gene rearrangements were somewhat differ-ent between the T and B lineage ALLs. In contrast, the lgHgene rearrangements were observed only in the B lineage ALL.The immunogenotype analysis of ALL proved to be a usefulmarker of the clonality and provided us with important informa-tion on early human lymphoid differentiation. We concludethat the determination of T
文摘Background Tumors with different gene expression develop and progress in different ways. To deepen our understanding of the progression in endometrial cancer, and provide a useful tool for accurate diagnosis and prognosis assessment, we identified the new molecular prognostic markers in endometrial carcinoma and analyzed the relationship of them with clinical and pathological features of endometrial carcinoma. Methods Ninety-four cases of endometrial endometrioid adenocarcinoma with complete data from the Peking University People＇s Hospital from 2000 to 2008 and 40 cases of normal endometrium were enrolled. Among these, 30 endometrial endometrioid adenocarcinoma samples of different International Federation of Gynecology and Obstetrics （FIGO） stage were selected for further Agilent genome-wide microarray analysis. Significance analysis of microarrays （SAM） was used to identify genes that are significantly associated with tumor progress. Immunohistochemistry was utilized to identify the genes of interest in endometrial carcinoma and normal endometrium. The relationship between the genes and the age, clinical stage, histological grade, myometrium invaded depth, lymph node metastasis status, and the expression of ER, PR, P53, and PTEN were analyzed by X2 test. Results Analysis between FIGO 1988 stage I and stage III identified a 362-gene ＂progress signature＂; 171 downregulated and 191 up-regulated genes. Among the alterative genes, TARP （T cell receptor gamma alternate reading frame protein） and KRT5 （keratin 5） decreased 3.57 fold and 5.8 fold in FIGO stage III patients. The expression of TARP in endometrial carcinoma increased compared to normal endometrium, while that of KRT5 decreased （P〈0.05）. The expression of TARP and KRT5 decreased when stage, histological grading, myometrium invaded depth increased （P〈0.05）. In the cases with lymph node metastasis, the expression of TARP decreased, while the expression of KRT5 did not differ （both P〈0.05） both. The expression of P53 had a negative relationship with the expression of KRT5 （P〈0.05）, but not with the expression of TARP （P〉0.05）. There was no correlation between the expression of TARP and KRT5 and the expression of ER, PR, PTEN （all P〉0.05）. There was no significant difference in TARP and KRT5 expression in patients aged 50 or younger and patients older than 50 （P〉0.05）. Conclusion The expression of TARP and KRT5 was correlated with the progress of endometrial cancer and their role needs further study.
