T cell receptor repertoire analysis of tumor-infiltrating T cells in non-small cell lung cancer [tumor_T_cells]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE151537 | GEO | 2021/03/11
REPOSITORIES: GEO
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Project description:We analyzed 778,938 T cell receptor (TCR) CDR3b sequences from 178 non-small cell lung cancer (NSCLC) patients using GLIPH2 (Grouping of Lymphocyte Interactions with Paratope Hotspots 2). We identified over 66,000 TCR shared specificity groups, of which over 400 were enriched in tumor vs. adjacent lung. We focused on one tumor-enriched specificity group and used a yeast display library to identify the peptide epitopes. These include peptides from TMEM161A, which is an overexpressed antigen in NSCLC, and homologous peptides from Epstein-Barr virus (EBV) and E. coli, aligning with recent reports of virus-specific T cells in tumor infiltrates. Overall, we analyzed a very large dataset of TCR sequences from NSCLC patients and found thousands of specificities shared by three or more patients. This creates a database of TCR shared specificity groups in NSCLC, and also a template for mining and understanding the specificity of infiltrating T cells for any cancer.
2021-03-11 | GSE151531 | GEO
Project description:ost characterized tumor antigens are ‘genomic’, i.e. encoded by canonical, non-canonical or somatically mutated genomic sequences. We investigate here the presentation and immunogenicity of tumor antigens derived from non-canonical mRNA splicing events between coding exons and transposable elements (TEs). Comparing non-small cell lung cancer (NSCLC), an immunogenic tumor type, and diverse non-tumor tissues, we identify several thousand splicing junctions between exons and diverse TE classes. A subset of these junctions is both tumor-specific and shared across patients. HLA-I peptidomic identifies peptides encoded by tumor-specific junctions in primary NSCLC samples and lung tumor cell lines. Recurrent junction-encoded peptides are immunogenic in vitro and CD8+ T cells specific for junction-encoded epitopes are present in tumors and tumor-draining lymph nodes from NSCLC patients. We conclude that non-canonical splicing junctions between exons and TEs represent a source of recurrent, immunogenic tumor-specific antigens in NSCLC cancer patients.
2023-02-27 | PXD034820 | Pride
Project description:Background: T-cell receptor (TCR) stimulation is essential to complete differentiation of tumor-infiltrating regulatory T cells (T-Tregs). Therefore, elucidation of TCR-dependent regulatory network involved in activation and proliferation of T-Tregs will facilitate discovery of novel antitumor remedy. Here, we investigated transcriptional features specific for antigen-reactive Tregs by harnessing single-cell RNA and TCR analyses of human Tregs derived from patients with non-small cell lung cancer (NSCLC). Methods: Assuming Tregs undergo clonal expansion in response to antigens, we sought for transcriptional features specific for antigen-reactive Tregs by comparing gene expression of Tregs with unique TCR clonotypes and those with expanded TCR clonotypes. To verify the identified molecule, multiplex immunohistochemistry and flow cytometry were used. Results: We found that the proportion of Tregs with expanded clonotypes was much higher in the tumor than in the periphery blood. We also found that T-Tregs with shared clonotypes were transcriptionally more similar to each other than to those with different clonotypes. Finally, we identified SYNGR2, TNFRSF18, DUSP4, and CTLA4 as core signature genes for T-Tregs with expanded clonotypes and confirmed their existences expressed on human T-Tregs. Interestingly, T-Treg-specific co-regulatory network revealed that SYNGR2, TNFRSF18 and DUSP4 are potential coordinators between TCR-dependent activation and cell proliferation. Conclusions: Our study shed light on regulatory insights of TCR-dependent Treg activation and differentiation in tumor and therapeutic strategies for patients with NSCLC.
2023-01-01 | GSE164146 | GEO
Project description:Infiltrating T-lymphocytes from the peripheral blood into the central nervous system (CNS) play a dynamic role in the development of a neurological immune-mediated diseases. HAM/TSP is a chronic progressive inflammatory neurological disorder associated with human T-cell lymphotropic virus type I (HTLV-I) infection. In this chronic myelopathy, virus-infected circulating T-cells infiltrate the CNS and an immune response is initiated against the components of CNS. As the HTLV-I proviral load (PVL) has been used as the best clinical marker for patient diagnostic with HAM/TSP, we hypothesized there might be a signature on T-cell receptor (TCR) clonal repertoire in these patients, which could distinguish HAM/TSP patients from the healthy population, as well as from patients with a more heterogeneous CNS-reactive inflammatory disease as multiple sclerosis (MS). With this in mind, we applied an innovative unbiased molecular technique – unique molecular identifier (UMI) library-strategy to investigate with high accuracy the TCR clonal repertoire by high throughput sequencing (HTS) technology. cDNA-TCR β-chain libraries were sequenced from 2 million peripheral mononuclear cells (PBMCs) in 14 HAM/TSP patients, 34 MS patients and 20 healthy controls (HC). To address whether the clonal expansion correlates with the patient’s PVL level, analysis of longitudinal TCR repertoire was performed in 2 HAM/TSP patients. Over 5.6 million TCR sequences were generated per sample on HiSeq 2500 Illumina system and analyzed through the molecular identifier groups-based error correction pipeline (MiGEC). Bioinformatic analysis showed that clones with more than 8 reads had a lower coefficient of variation (CV) and then could be used with confidence to evaluate the TCR clonal expansion. While HAM/TSP patients showed the higher clonal T-cell expansion compared to MS and HC, increase of the TCR clonal expansion was inversely correlated with the diversity of TCR repertoire in all subject’s group. In addition, correlation of the PVL with TCR clonal expansion was observed in HAM/TSP patients at longitudinal time-points. Surprisingly, MS patients showed a higher diversity of TCR repertoire along with a very slight clonal T-cell expansion in comparison to either HAM/TSP patients or HC. Despite of the higher TCR clonal expansion in HAM/TSP patients, a non-shared or “private” TCR repertoire was observed in these patients. No clones that shared the same CDR3 amino acid sequences were seen in HC and MS patients. However, a cluster of related CDR3 amino acid sequences were observed for 18 out of 34 MS patients when evaluated by phylogenetic tree analysis. It suggestes that a TCR-repertoire signature might characterize patients with MS. Our findings suggest that even though a unique TCR-b repertoire shapes the immune response in patients with neurological immune-mediated disease, a relatedness on clonal T-cell repertoire exist in MS.
2019-01-29 | GSE121082 | GEO
Project description:Despite the conventional view that a truly random V(D)J recombination process should generate a highly diverse immune repertoire, emerging reports suggest that there is a certain bias towards the generation of shared/public immune receptor chains. These studies were performed in viral diseases where public T-cell receptors (TCR) appear to confer better protective responses. Selective pressures generating common TCR clonotypes are currently not well understood but it is believed that they confer a growth advantage. As very little is known about public TCR clonotypes in cancer, here we set out to determine the extent of shared TCR clonotypes in the intra-tumor microenvironments of virus- and non-virus- driven head and neck cancers using TCR sequencing. We report that tumor-infiltrating T-cell clonotypes were indeed shared across individuals with the same cancer type, where the majority of shared sequences were specific to the cancer type (ie viral versus non-viral). These shared clonotypes were not particularly enriched in EBV-associated nasopharynx cancer, but in both cancers, exhibited distinct characteristics, namely shorter CDR3 lengths, restricted V- and J-gene usages and also demonstrated convergent V(D)J recombination. Many of these shared TCRs were expressed in patients with a shared HLA background. Pattern recognition of CDR3 amino acid sequences revealed strong convergence to specific motifs that were unique to each cancer type, suggesting they may be enriched for specificity to common antigens found in the tumor microenvironment. The identification of shared TCRs in infiltrating tumor T-cells not only adds to our understanding of the tumor adaptive immune recognition but could also serve as disease-specific biomarkers and guide the development of future immunotherapies.
| EGAS00001005480 | EGA
Project description:Background: Anti-tumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences. Methods: We developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous anti-tumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes. Results: We discovered that genetically identical wild-type recipient mice responded heterogeneously to the same SCC tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous anti-tumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRa/TCRb sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing vs. growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status. Conclusions: We reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous anti-tumor immune responses in different hosts. We suggest that anti-tumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.
2021-01-13 | GSE164153 | GEO
Project description:Our hypothesis is that a major fraction of the expanded clones of T lymphocytes in the cerebrospinal fluid (CSF) are specific for autologous EBV-infected B cells. We obtained blood and CSF samples from 8 relapsing-remitting patients in the process of diagnosis. We stimulated cells from the blood with autologous EBV-infected lymphoblastoid cell lines (LCL), EBV, varicella zoster virus, influenza, and candida, and sorted the responding cells with flow cytometry after 6 days. We sequenced the RNA for T cell receptors (TCR) from CSF, unselected blood cells, and the antigen-specific cells. We used the TCR Vβ CDR3 sequences from the antigen-specific cells to assign antigen specificity to the sequences from the CSF and blood. LCL-specific cells comprised 13.0±4.3% (mean±standard deviation) of the total reads present in CSF and 13.3±7.5% of the reads present in blood. The next most abundant antigen specificity was flu, which was 4.7±1.7% of the reads in the CSF and 9.3±6.6% in the blood. The prominence of LCL-specific reads was even more marked in the top 1% most abundant CSF clones with statistically significant 47% mean overlap with LCL.
2023-12-19 | GSE250037 | GEO
Project description:We report a 29-gene diagnostic signature, which distinguishes individuals with NSCLC from controls with non-malignant lung disease with 91% Sensitivity, 79% Specificity and a ROC AUC of 92%. Accuracy on an independent set of 18 NSCLC samples from the same location was 79%. Samples from an independent location including 12 stage 1 NSCLC and 15 controls, achieved an accuracy of 74%. A study of 18 paired samples taken pre and post surgery shows that the PBMC associated â??cancerâ?? signature is significantly reduced after tumor removal, supporting the hypothesis that the signature detected in pre-surgery samples is a response to the presence of the tumor. We compared microarray gene expression profiles in PBMC from patients with NSCLC and a control group with smoking-related non-malignant lung disease, a likely confounding factor. We found a distinguishing gene signature which was validated on 2 independent sets of hold-out samples one set from a different location. Gene expression changes were also compared between pre and post surgery samples from 18 patients.
2010-04-09 | E-GEOD-13255 | biostudies-arrayexpress
Project description:Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.
2023-12-01 | GSE248401 | GEO