TCR-like bispecific antibodies toward eliminating infected hepatocytes in HBV mouse models.

Therapeutics for eradicating hepatitis B virus (HBV) infection are still limited and current nucleos(t)ide analogs (NAs) and interferon are effective in controlling viral replication and improving liver health, but they cannot completely eradicate the hepatitis B virus and only a very small number of patients are cured of it. The TCR-like antibodies recognizing viral peptides presented on human leukocyte antigens (HLA) provide possible tools for targeting and eliminating HBV-infected hepatocytes. Here, we generated three TCR-like antibodies targeting three different HLA-A2.1-presented peptides derived from HBV core and surface proteins. Bispecific antibodies (BsAbs) were developed by fuzing variable fragments of these TCR-like mAbs with an anti-CD3ϵ antibody. Our data demonstrate that the BsAbs could act as T cell engagers, effectively redirecting and activating T cells to target HBV-infected hepatocytes in vitro and in vivo. In HBV-persistent mice expressing human HLA-A2.1, two infusions of BsAbs induced marked and sustained suppression in serum HBsAg levels and also reduced the numbers of HBV-positive hepatocytes. These findings highlighted the therapeutic potential of TCR-like BsAbs as a new strategy to cure hepatitis B.

Case report: An intriguing case of Philadelphia chromosome-positive acute lymphoblastic leukemia recurrence.

The incorporation of tyrosine kinase inhibitors (TKIs) in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) led to significant improvement. However, in the pediatric setting, the outcomes of Ph+ ALL are still inferior compared to those of other ALL subtypes even in the TKI era due to higher relapse rate. Herein, we report a very peculiar case of late extramedullary Ph+ ALL relapse in a child, characterized by lymphomatous presentation in the tonsils and lymphoid lineage switch. The diagnostic dilemma between the occurrence of a second malignant neoplasm and the recurrence of the primary disease is further discussed, highlighting the importance of molecular backtracking analysis. This case report emphasizes the high plasticity and polyclonal nature of ALL and expands the heterogeneity of possible clinical presentation of Ph+ ALL at relapse.

Predicting T cell receptor functionality against mutant epitopes.

Cancer cells and pathogens can evade T cell receptors (TCRs) via mutations in immunogenic epitopes. TCR cross-reactivity (i.e., recognition of multiple epitopes with sequence similarities) can counteract such escape but may cause severe side effects in cell-based immunotherapies through targeting self-antigens. To predict the effect of epitope point mutations on T cell functionality, we here present the random forest-based model Predicting T Cell Epitope-Specific Activation against Mutant Versions (P-TEAM). P-TEAM was trained and tested on three datasets with TCR responses to single-amino-acid mutations of the model epitope SIINFEKL, the tumor neo-epitope VPSVWRSSL, and the human cytomegalovirus antigen NLVPMVATV, totaling 9,690 unique TCR-epitope interactions. P-TEAM was able to accurately classify T cell reactivities and quantitatively predict T cell functionalities for unobserved single-point mutations and unseen TCRs. Overall, P-TEAM provides an effective computational tool to study T cell responses against mutated epitopes.

Inhibition of PCSK9 enhances the anti-hepatocellular carcinoma effects of TCR-T cells and anti-PD-1 immunotherapy.

T cells play important roles in antitumor immunity. However, given that the hepatocellular carcinoma (HCC) tumor microenvironment confers resistance to T cell-based immunotherapies, novel strategies to boost T cell-mediated antitumor efficacy are urgently needed for the treatment of HCC. Here, we show that high proprotein convertase subtilisin/kexin type9 (PCSK9) expression was negatively associated with HCC patient's overall survival and markers of CD8+ T cells. Pharmacological inhibition of PCSK9 enhanced tumor-specific killing and downregulated PD-1 expression of AFP-specific TCR-T. Inhibition of PCSK9 significantly enhances the anti-HCC efficacy of TCR-T cells and anti-PD-1 immunotherapy in vivo. Moreover, PCSK9 inhibitor suppressed HCC growth dependent on CD8+ T cells. Mechanically, pharmacological inhibition of PCSK9 promoted low-density lipoprotein receptor (LDLR)-mediated activation of mTORC1 signaling in CD8+ T cells. LDLR deficiency was shown to impair cellular mTORC1 signaling and the anti-HCC function of CD8 T cells. On the basis of our findings in this study, we propose a potential metabolic intervention strategy that could be used to enhance the antitumor effects of immunotherapy for HCC.

Calcineurin is an adaptor required for assembly of the TCR signaling complex.

The serine/threonine phosphatase calcineurin is a component of the T cell receptor (TCR) signalosome, where it promotes T cell activation by dephosphorylating LckS59. Using small interfering RNA (siRNA)-mediated knockdown and CRISPR-Cas9-targeted genetic disruption of the calcineurin A chain α and ß isoforms, we find that calcineurin also functions as an adaptor in TCR-signaled human T cells. Unlike inhibition of its phosphatase activity, in the absence of calcineurin A, TCR signaling results in attenuated actin rearrangement, markedly reduced TCR-Lck microcluster formation and recruitment of the adaptor RhoH, and diminished phosphorylation of critical targets downstream of Lck such as TCRζ and ZAP-70. Reconstitution of deficient T cells with either calcineurin Aα or Aß restores TCR microcluster formation and signaling, as does reconstitution with a phosphatase-inactive Aα chain. These results assign a non-enzymatic adaptor function to calcineurin in the formation and stabilization of a functional TCR signaling complex.

TCR clustering by contrastive learning on antigen specificity.

Effective clustering of T-cell receptor (TCR) sequences could be used to predict their antigen-specificities. TCRs with highly dissimilar sequences can bind to the same antigen, thus making their clustering into a common antigen group a central challenge. Here, we develop TouCAN, a method that relies on contrastive learning and pretrained protein language models to perform TCR sequence clustering and antigen-specificity predictions. Following training, TouCAN demonstrates the ability to cluster highly dissimilar TCRs into common antigen groups. Additionally, TouCAN demonstrates TCR clustering performance and antigen-specificity predictions comparable to other leading methods in the field.

Characteristics of T-Cell Receptor Repertoire for Differential Response to Methotrexate Treatment for Rheumatoid Arthritis.

BACKGROUND: Methotrexate (MTX) serves as the initial treatment for rheumatoid arthritis (RA). However, a substantial proportion of RA patients, estimated between 30% and 50%, do not respond positively to MTX. While the T-cell receptor (TCR) is crucial for the immune response during RA, its role in differentiating MTX responsiveness has not been thoroughly investigated. METHODS: This study used next-generation sequencing to analyze the TCR ß-chain complementary determining region sequences in peripheral blood mononuclear cells obtained from RA patients before MTX treatment. This study aimed to compare the characteristics of the TCR repertoire between the MTX responder and non-responder groups. RESULTS: The study identified a significant difference in the TRBV6-6 gene (p = .003) concerning MTX treatment response. Additionally, a significant difference was found in the number of "3" nucleotide deletions at the 5'Jdels site (p = .023) in the VDJ rearrangement. CONCLUSION: These findings suggest distinct TCR repertoire characteristics between MTX responder and non-responder groups among RA patients. This discovery offers new insights into understanding the variable responses of RA patients to MTX therapy.

The active form of vitamin D (calcitriol) promotes CXCR5 expression during follicular helper T cell differentiation.

Follicular helper T (Tfh) cells promote B cell differentiation and antibody production in the B cell follicles of secondary lymphoid organs. Tfh cells express their signature transcription factor BCL6, interleukin (IL)-21, and surface molecules including inducible T cell costimulator, programmed cell death-1 (PD-1), and the chemokine receptor CXCR5. Migration of Tfh cells to B cell follicles largely depends on the CXCR5 expression induced by interactions with antigen-presenting dendritic cells in the T cell area. How Tfh cells acquire sufficient levels of CXCR5 expression, however, has remained unclear. Using our in vitro culture system to generate CXCR5low Tfh-like cells from naïve CD4+ T cells with IL-6 in the absence of other cell types, we found that the active form of vitamin D, calcitriol, markedly enhanced CXCR5 expression after the release from persistent T cell receptor (TCR) stimulation. CH-223191, an aryl hydrocarbon receptor antagonist, further enhanced CXCR5 expression. IL-12 but not IL-4, in place of IL-6, also supported calcitriol to enhance CXCR5 expression even before the release from TCR stimulation, whereas the cell viability sharply decreased after the release. The Tfh-like cells generated with IL-6 and calcitriol exhibited chemotaxis towards CXCL13, expressed IL-21, and helped B cells to produce IgG antibodies in vitro more efficiently than Tfh-like cells generated without added calcitriol. Calcitriol injections into antigen-primed mice increased the proportion of CXCR5+PD-1+CD4+ cells in their lymphoid organs, and enhanced T cell entry into B-cell follicles. These results suggest that calcitriol promotes CXCR5 expression in developing Tfh cells and regulates their functional differentiation.

Immune cell reconstitution following autologous hematopoietic stem cell transplantation in multiple sclerosis.

Hematopoietic stem cell transplantation (HSCT) is a multistep procedure aimed at eradicating the immune system and replacing it with a new one reconstituted from hematopoietic stem cells which in autologous HSCT (AHSCT) have previously been harvested from the same individual. Over the last two decades, AHSCT has been developed as a treatment option for people affected by aggressive multiple sclerosis (MS), and it exerts a long-standing effect on new inflammation-driven disease activity. The rationale for the use of AHSCT in MS will be discussed, starting from the first observations on experimental models. The mechanisms and kinetics of repopulation (i.e., quantitative recovery) and reconstitution (i.e., qualitative changes) of the immune cell populations will be explored, focusing on immune reconstitution of the T and B cells compartments and briefly covering changes in the innate immune system. Finally, potential immunologic markers of response to treatment will be reviewed. Insights into the supposed mechanism(s) of action of AHSCT will be provided, discussing the leading hypothesis of the "rebuilding" of a newly tolerant immune system, and examining the apparent paradox of the long-standing control of disease activity despite a relatively short-term immunosuppressive effect of the procedure.

Mathematical models of TCR initial triggering.

T cell receptors (TCRs) play crucial roles in regulating T cell response by rapidly and accurately recognizing foreign and non-self antigens. The process involves multiple molecules and regulatory mechanisms, forming a complex network to achieve effective antigen recognition. Mathematical modeling techniques can help unravel the intricate network of TCR signaling and identify key regulators that govern it. In this review, we introduce and briefly discuss relevant mathematical models of TCR initial triggering, with a focus on kinetic proofreading (KPR) models with different modified structures. We compare the topology structures, biological hypotheses, parameter choices, and simulation performance of each model, and summarize the advantages and limitations of them. Further studies on TCR modeling design, aiming for an optimized balance of specificity and sensitivity, are expected to contribute to the development of new therapeutic strategies.

Predicting Antigen-Specificities of Orphan T Cell Receptors from Cancer Patients with TCRpcDist.

Approaches to analyze and cluster T-cell receptor (TCR) repertoires to reflect antigen specificity are critical for the diagnosis and prognosis of immune-related diseases and the development of personalized therapies. Sequence-based approaches showed success but remain restrictive, especially when the amount of experimental data used for the training is scarce. Structure-based approaches which represent powerful alternatives, notably to optimize TCRs affinity toward specific epitopes, show limitations for large-scale predictions. To handle these challenges, TCRpcDist is presented, a 3D-based approach that calculates similarities between TCRs using a metric related to the physico-chemical properties of the loop residues predicted to interact with the epitope. By exploiting private and public datasets and comparing TCRpcDist with competing approaches, it is demonstrated that TCRpcDist can accurately identify groups of TCRs that are likely to bind the same epitopes. Importantly, the ability of TCRpcDist is experimentally validated to determine antigen specificities (neoantigens and tumor-associated antigens) of orphan tumor-infiltrating lymphocytes (TILs) in cancer patients. TCRpcDist is thus a promising approach to support TCR repertoire analysis and TCR deorphanization for individualized treatments including cancer immunotherapies.

The reverse TRBV30 gene of mammals: a defect or superiority in evolution?

At the 3' end of the C2 gene in the mammalian TRB locus, a distinct reverse TRBV30 gene (named TRBV31 in mice) has been conserved throughout evolution. In the fully annotated TRB locus of 14 mammals (including six orders), we observed noteworthy variations in the localization and quality of the reverse V30 genes and Recombination Signal Sequences (RSSs) in the gene trees of 13 mammals. Conversely, the forward V29 genes and RSSs were generally consistent with the species tree of their corresponding species. This finding suggested that the evolution of the reverse V30 gene was not synchronous and likely played a crucial role in regulating adaptive immune responses. To further investigate this possibility, we utilized single-cell TCR sequencing (scTCR-seq) and high-throughput sequencing (HTS) to analyze TCRß CDR3 repertoires from both central and peripheral tissues of Primates (Homo sapiens and Macaca mulatta), Rodentia (Mus musculus: BALB/c, C57BL/6, and Kunming mice), Artiodactyla (Bos taurus and Bubalus bubalis), and Chiroptera (Rhinolophus affinis and Hipposideros armige). Our investigation revealed several novel observations: (1) The reverse V30 gene exhibits classical rearrangement patterns adhering to the '12/23 rule' and the 'D-J rearrangement preceding the V-(D-J) rearrangement'. This results in the formation of rearranged V30-D2J2, V30-D1J1, and V30-D1J2. However, we also identified 'special rearrangement patterns' wherein V30-D rearrangement preceding D-J rearrangement, giving rise to rearranged V30-D2-J1 and forward Vx-D2-J. (2) Compared to the 'deletional rearrangement' (looping out) of forward V1-V29 genes, the reverse V30 gene exhibits preferential utilization with 'inversional rearrangement'. This may be attributed to the shorter distance between the V30 gene and D gene and the 'inversional rearrangement' modes. In summary, in the mammalian TRB locus, the reverse V30 gene has been uniquely preserved throughout evolution and preferentially utilized in V(D)J recombination, potentially serving a significant role in adaptive immunity. These results will pave the way for novel and specialized research into the mechanisms, efficiency, and function of V(D)J recombination in mammals.

A structural basis of T cell cross-reactivity to native and spliced self-antigens presented by HLA-DQ8.

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that has a strong HLA association, where a number of self-epitopes have been implicated in disease pathogenesis. Human pancreatic islet-infiltrating CD4+ T cell clones not only respond to proinsulin C-peptide (PI40-54; GQVELGGGPGAGSLQ) but also cross-react with a hybrid insulin peptide (HIP; PI40-47-IAPP74-80; GQVELGGG-NAVEVLK) presented by HLA-DQ8. How T cell receptors recognise self-peptide and cross-react to HIPs is unclear. We investigated the cross-reactivity of the CD4+ T cell clones reactive to native PI40-54 epitope and multiple HIPs fused at the same N-terminus (PI40-54) to the degradation products of two highly expressed pancreatic islet proteins, Neuropeptide Y (NPY68-74) and amyloid polypeptide (IAPP23-29 and IAPP74-80). We observed that five out of the selected SKW3 T cell lines expressing TCRs isolated from CD4+ T cells of people with T1D responded to multiple HIPs. Despite shared TRAV26-1-TRBV5-1 gene usage in some T cells, these clones cross-reacted to varying degrees with the PI40-54 and HIP epitopes. Crystal structures of two TRAV26-1+-TRBV5-1+ T cell receptors (TCRs) in complex with PI40-54 and HIPs bound to HLA-DQ8 revealed that the two TCRs had distinct mechanisms responsible for their differential recognition of the PI40-54 and HIP epitopes. Alanine scanning mutagenesis of the PI40-54 and HIPs determined that the P2, P7 and P8 residues in these epitopes were key determinants of TCR specificity. Accordingly, we provide a molecular basis for cross-reactivity towards native insulin and HIP epitopes presented by HLA-DQ8.

Sepsis shapes the human γδ TCR repertoire in an age- and pathogen-dependent manner.

Sepsis affects 25 million children per year globally, leading to 2.9 million deaths and substantial disability in survivors. Extensive characterization of interactions between the host and bacteria in children is required to design novel preventive and therapeutic strategies tailored to this age group. Vγ9Vδ2 T cells are the first T cells generated in humans. These cells are defined by the expression of Vγ9Vδ2 T-cell receptors (TCRs, using the TRGV9 and TRDV2 gene segments), which react strongly against the prototypical bacterial phosphoantigen HMBPP. We investigated this reactivity by analyzing the TCR δ (TRD) repertoire in the blood of 76 children (0-16 years) with blood culture-proven bacterial sepsis caused by HMBPP-positive Escherichia coli or by HMBPP-negative Staphylococcus aureus or by HMBPP-negative Streptococcus pneumoniae. Strikingly, we found that S. aureus, and to a lesser extent E. coli but not S. pneumoniae, shaped the TRDV2 repertoire in young children (<2 years) but not in older children or adults. This dichotomy was due to the selective expansion of a fetal TRDV2 repertoire. Thus, young children possess fetal-derived Vγ9Vδ2 T cells that are highly responsive toward specific bacterial pathogens.

PTPN22 through the regulation of Th17/Treg balance acts as a potential target for the treatment of Graves' disease.

Graves' disease (GD) is an autoimmune disease and the most common cause of hyperthyroidism. While the phosphotyrosine phosphatase non-receptor type 22 (PTPN22) variant is associated with GD susceptibility, its precise role and mechanism in GD remain unclear. To investigate this, we induced GD in mice using Ad-TSHR289 and isolated CD4+ T cells from spleen tissues. We conducted a series of experiments, including hematoxylin-eosin staining, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, flow cytometry, immunofluorescence (IF), reverse transcription quantitative PCR (RT-qPCR), and western blotting. PTPN22 expression was found to be downregulated in GD mice. Overexpression of PTPN22 ameliorated pathological damage and increased serum levels of T4 and thyroid stimulating hormone receptor antibody (TRAb), as well as the ratio of thyroid weight to body weight in GD mice. Furthermore, GD mice exhibited elevated levels of CD4+ and IL-17+ T cells, an increased Th17/Treg ratio, and upregulation of IL-17A mRNA expression. Conversely, there was a decrease in Foxp3+ T cells and transcriptional levels of Foxp3, which were reversed by PTPN22 overexpression. In vitro experiments showed that PTPN22 overexpression in CD4+ T cells from spleen tissues of GD mice enhanced Foxp3 expression while reducing IL-17A expression. Mechanistically, PTPN22 overexpression led to decreased levels of phosphorylated Lck (p-Lck), Lck, phosphorylated Fyn (p-Fyn), Fyn, phosphorylated Zap70 (p-Zap70), and Zap70 in both in vivo and in vitro GD models. In summary, PTPN22 can alleviate thyroid dysfunction in GD by modulating Th17/Treg balance through the downregulation of the Lck/Zap70 signaling axis.

Genomic analysis and identification of a novel superantigen, SargEY, in Staphylococcus argenteus isolated from atopic dermatitis lesions.

During surveillance of Staphylococcus aureus in lesions from patients with atopic dermatitis (AD), we isolated Staphylococcus argenteus, a species registered in 2011 as a new member of the genus Staphylococcus and previously considered a lineage of S. aureus. Genome sequence comparisons between S. argenteus isolates and representative S. aureus clinical isolates from various origins revealed that the S. argenteus genome from AD patients closely resembles that of S. aureus causing skin infections. We previously reported that 17%-22% of S. aureus isolated from skin infections produce staphylococcal enterotoxin Y (SEY), which predominantly induces T-cell proliferation via the T-cell receptor (TCR) Vα pathway. Complete genome sequencing of S. argenteus isolates revealed a gene encoding a protein similar to superantigen SEY, designated as SargEY, on its chromosome. Population structure analysis of S. argenteus revealed that these isolates are ST2250 lineage, which was the only lineage positive for the SEY-like gene among S. argenteus. Recombinant SargEY demonstrated immunological cross-reactivity with anti-SEY serum. SargEY could induce proliferation of human CD4+ and CD8+ T cells, as well as production of TNF-α and IFN-γ. SargEY showed emetic activity in a marmoset monkey model. SargEY and SET (a phylogenetically close but uncharacterized SE) revealed their dependency on TCR Vα in inducing human T-cell proliferation. Additionally, TCR sequencing revealed other previously undescribed Vα repertoires induced by SEH. SargEY and SEY may play roles in exacerbating the respective toxin-producing strains in AD. IMPORTANCE: Staphylococcus aureus is frequently isolated from active lesions of atopic dermatitis (AD) patients. We reported that 17%-22% of S. aureus isolated from AD patients produced a novel superantigen staphylococcal enterotoxin Y (SEY). Unlike many S. aureus superantigens that activate T cells via T-cell receptor (TCR) Vß, SEY activates T cells via TCR Vα and stimulates cytokine secretion. Staphylococcus argenteus was isolated from AD patients during the surveillance for S. aureus. Phylogenetic comparison of the genome indicated that the isolate was very similar to S. aureus causing skin infections. The isolate encoded a SEY-like protein, designated SargEY, which, like SEY, activated T cells via the TCR Vα. ST2250 is the only lineage positive for SargEY gene. ST2250 S. argenteus harboring a superantigen SargEY gene may be a novel staphylococcal clone that infects human skin and is involved in the exacerbation of AD.

Liposome-based in situ antigen-modification strategy for "universal" T-cell-receptor engineered T cell in cancer immunotherapy.

T-cell receptor (TCR) engineered T-cell therapy, unlike chimeric antigen receptor T-cell therapy, relies on the inherent ability of TCRs to detect a wider variety of antigenic epitopes, such as protein fragments found internally or externally on cells. Hence, TCR-T-cell therapy offers broader possibilities for treating solid tumors. However, because of the complicated process of identifying specific antigenic peptides, their clinical application still encounters significant challenges. Thus, we aimed to establish a novel "universal" TCR-T "artificial antigen expression" technique that involves the delivery of the antigen to tumor cells using DSPE-PEG-NY-ESO-1157-165 liposomes (NY-ESO-1 Lips) to express TCR-T-cell-specific recognition targets. In vitro as well as in vivo studies revealed that they could accumulate efficiently in the tumor area and deliver target antigens to activate the tumor-specific cytotoxic T-cell immune response. NY-ESO-1 TCR-T therapy, when used in combination, dramatically curbed tumor progression and extended the longevity of mice. Additionally, PD-1 blockage enhanced the therapeutic effect of the aforementioned therapy. In conclusion, NY-ESO-1 Lips "cursed" tumor cells by enabling antigenic target expression on their surface. This innovative technique presents a groundbreaking approach for the widespread utilization of TCR-T in solid tumor treatment.

Exploring the potential of the TCR repertoire as a tumor biomarker (Review).

T cells play an important role in adaptive immunity. Mature T cells specifically recognize antigens on major histocompatibility complex molecules through T-cell receptors (TCRs). As the TCR repertoire is highly diverse, its analysis is vital in the assessment of T cells. Advances in sequencing technology have provided convenient methods for further investigation of the TCR repertoire. In the present review, the TCR structure and the mechanisms by which TCRs function in tumor recognition are described. In addition, the potential value of the TCR repertoire in tumor diagnosis is reviewed. Furthermore, the role of the TCR repertoire in tumor immunotherapy is introduced, and the relationships between the TCR repertoire and the effects of different tumor immunotherapies are discussed. Based on the reviewed literature, it may be concluded that the TCR repertoire has the potential to serve as a biomarker for tumor prognosis. However, a wider range of cancer types and more diverse subjects require evaluation in future research to establish the TCR repertoire as a biomarker of tumor immunity.

Comprehensive application of AI algorithms with TCR NGS data for glioma diagnosis.

T-cell receptor (TCR) detection can examine the extent of T-cell immune responses. Therefore, the article analyzed characteristic data of glioma obtained by DNA-based TCR high-throughput sequencing, to predict the disease with fewer biomarkers and higher accuracy. We downloaded data online and obtained six TCR-related diversity indices to establish a multidimensional classification system. By comparing actual presence of the 602 correlated sequences, we obtained two-dimensional and multidimensional datasets. Multiple classification methods were utilized for both datasets with the classification accuracy of multidimensional data slightly less to two-dimensional datasets. This study reduced the TCR ß sequences through feature selection methods like RFECV (Recursive Feature Elimination with Cross-Validation). Consequently, using only the presence of these three sequences, the classification AUC value of 96.67% can be achieved. The combination of the three correlated TCR clones obtained at a source data threshold of 0.1 is: CASSLGGNTEAFF_TRBV12_TRBJ1-1, CASSYSDTGELFF_TRBV6_TRBJ2-2, and CASSLTGNTEAFF_TRBV12_TRBJ1-1. At 0.001, the combination is: CASSLGETQYF_TRBV12_TRBJ2-5, CASSLGGNQPQHF_TRBV12_TRBJ1-5, and CASSLSGNTIYF_TRBV12_TRBJ1-3. This method can serve as a potential diagnostic and therapeutic tool, facilitating diagnosis and treatment of glioma and other cancers.