Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1040464 | ENA |
REPOSITORIES: ENA
Similar Datasets
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
Project description:Personalized cancer vaccines aim to activate and expand cytotoxic anti-tumor CD8+ T cells to recognize and kill tumor cells. However, the role of CD4+ T cell activation in the clinical benefit of these vaccines is not well defined. We previously established a personalized neoantigen vaccine (PancVAX) for the pancreatic cancer cell line Panc02, which activates tumor-specific CD8+ T cells but required combinatorial checkpoint modulators to achieve therapeutic efficacy. To determine the effects of neoantigen-specific CD4+ T cell activation, we generated a new vaccine (PancVAX2) targeting both MHCI- and MHCII-specific neoantigens. Tumor-bearing mice vaccinated with PancVAX2 had significantly improved control of tumor growth and long-term survival benefit without concurrent administration of checkpoint inhibitors. PancVAX2 significantly enhanced priming and recruitment of neoantigen-specific CD8+ T into the tumor with lower PD1 expression after reactivation compared to the CD8+ vaccine alone. Vaccine-induced neoantigen- specific Th1 CD4+ T cells in the tumor were associated with decreased T regulatory cells (Tregs). Consistent with this, PancVAX2 was associated with more pro-immune myeloid-derived suppressor cells and M1-like macrophages in the tumor demonstrating a less immunosuppressive tumor microenvironment. This study demonstrates the biological importance of prioritizing and including CD4 T cell-specific neoantigens for personalized cancer vaccine modalities.
2023-12-11 | GSE244992 | GEO
Project description:Neoantigen discovery in pediatric brain tumors is hampered by their low mutational burden and scant tissue availability. We developed a low-input proteogenomic approach combining tumor DNA/RNA sequencing and mass spectrometry proteomics to identify tumor-restricted (neoantigen) peptides arising from multiple genomic aberrations to generate a highly target-specific, autologous, personalized T cell immunotherapy. Our data indicate that novel splice junctions are the primary source of neoantigens in medulloblastoma, a common pediatric brain tumor. Proteogenomically identified tumor-specific peptides are immunogenic and generate MHC II-based T cell responses. Moreover, polyclonal and polyfunctional T cells specific for tumor-specific peptides effectively eliminated tumor cells in vitro. Targeting novel tumor-specific antigens obviates the issue of central immune tolerance while potentially providing a safety margin favoring combination with other immune-activating therapies. These findings demonstrate the proteogenomic discovery of immunogenic tumor-specific peptides and lay the groundwork for personalized targeted T cell therapies for children with brain tumors.
2021-11-02 | PXD029082 | Pride
Project description:The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using two novel preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, which are similar to tumor-infiltrating lymphocytes of human PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical to maintain immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.
2021-07-25 | GSE163059 | GEO
Project description:A patient (4095) with metastatic colorectal cancer was treated with polyclonal tumor infiltrating lymphocytes (TILs) targeting the KRAS(G12D) hotspot mutation. Three dominant clonotypes specifically recognizing KRAS(G12D) epitopes were identified, but we found that only two clonotypes persisted 40 days after TIL treatment. Because of these findings, in this study, we utilized a 10X system to perform single-cell TCR/transcriptome analysis for the TILs isolated from this patient, together with 4 additional TILs isolated from 4 patients (4007, 4069, 4071, 4081) treated within 5-month window. In addition, we performed single-cell TCR/transcriptome analysis on Patient 4095's peripheral blood lymphocytes (PBL) day 12 or day 40 after TIL treatment. We also utilized a low-throughput Fluidigm C1 system to perform single-cell RNA-Seq on TIL4095. Please use accession number GSE136610 to find the dataset.
2019-09-10 | GSE136394 | GEO
Project description:Metastatic uveal melanoma generally responds poorly to immunotherapy. The aim here was to sequence tumor-infiltrating lymphocytes from uveal melanoma metastases to study their phenotypes and T-cell receptor (TCR) clonotypes. We performed paired single-cell transcriptome and TCR sequencing using the 10x Genomics platform of IL2-expanded tumor-infiltrating lymphocytes from 7 liver and 1 subcutaneous metastasis.
2020-03-16 | E-MTAB-8846 | biostudies-arrayexpress
Project description:We wished to examine early transcriptional changes that occur after TCR engagement in CD8+ cytotoxic T lymphocytes (CTLs). To this end, we differentiated effector CTLs from OTI TCR transgenic mice for 7 days in vitro and then stimulated them with anti-CD3 for various times before lysing for RNA-seq. Results demonstrated significant transcriptional changes starting from 20 minutes. After 60 minutes, upregulated genes were most enriched for cytokines and transcriptional machinery.
2023-10-15 | E-MTAB-12083 | biostudies-arrayexpress
Project description:The success of cancer immunotherapy depends in part on the strength of antigen recognition by T cells. We characterized the T cell receptor (TCR) functional (antigen sensitivity) and structural (monomeric pMHC-TCR off-rates) avidities of 371 CD8 T cell clones specific for neoantigens, tumor-associated antigens (TAAs) or viral antigens isolated from tumors or blood of patients and healthy subjects. T cells from tumors exhibit stronger functional and structural avidity than their blood counterparts. Relative to TAA, neoantigen-specific T cells are of higher structural avidity and, consistently, are preferentially detected in tumors. Effective tumor infiltration in mice models is associated with high structural avidity and CXCR3 expression. Based on TCRs biophysicochemical properties, we derived and applied an in silico model predicting TCR structural avidity and validated the enrichment in high avidity T cells in patients’ tumors. These observations indicate a direct relationship between neoantigen recognition, T cell functionality and tumor infiltration. These results delineate a rational approach to identify potent T cells for personalized cancer immunotherapy.
2023-05-18 | GSE232446 | GEO
Project description:The success of cancer immunotherapy depends in part on the strength of antigen recognition by T cells. We characterized the T cell receptor (TCR) functional (antigen sensitivity) and structural (monomeric pMHC-TCR off-rates) avidities of 371 CD8 T cell clones specific for neoantigens, tumor-associated antigens (TAAs) or viral antigens isolated from tumors or blood of patients and healthy subjects. T cells from tumors exhibit stronger functional and structural avidity than their blood counterparts. Relative to TAA, neoantigen-specific T cells are of higher structural avidity and, consistently, are preferentially detected in tumors. Effective tumor infiltration in mice models is associated with high structural avidity and CXCR3 expression. Based on TCRs biophysicochemical properties, we derived and applied an in silico model predicting TCR structural avidity and validated the enrichment in high avidity T cells in patients’ tumors. These observations indicate a direct relationship between neoantigen recognition, T cell functionality and tumor infiltration. These results delineate a rational approach to identify potent T cells for personalized cancer immunotherapy.
2023-05-18 | GSE232444 | GEO
Project description:Effector cytotoxic T lymphocytes (CTLs) are critical for ridding the body of infected or cancerous cells. Recognition of an antigenic ligand by the CTL’s T cell receptor (TCR) triggers a signalling cascade that ultimately results in the targeted release of cytolytic granules and/or secretion of cytokines and chemokines to alert and recruit additional immune cells. These signalling cascades are capable of initiating transcription, translation, and cytoskeletal rearrangements. While previous work has demonstrated how translation and intracellular reorganisation contribute to CTL effector responses, the role of transcription is less well studied. To address this, we examined the impact of blocking transcription on the CTL proteome during TCR stimulation. These data demonstrated a strong transcriptional requirement for expression of cytokines and chemokines but not cytolytic molecules. Together with functional studies, these data reveal differential molecular control of the cell-cell communication and cytolytic functions of effector CTLs. CTLs exhibit complete and persistent priming for cytolytic activity prior to target cell encounter, but they require de novo transcription to recruit additional immune cells that amplify the response.
2023-10-16 | PXD034920 | Pride