Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Neoantigen-Specific CD8 T Cells with High Structural Avidity Preferentially Reside in and Eliminate Tumors (VDJ)

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE232446 | GEO | 2023/05/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Neoantigen-Specific CD8 T Cells with High Structural Avidity Preferentially Reside in and Eliminate Tumors (GEX)

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

Personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against metastatic ovarian cancer

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

Signatures of recent activation identify a circulating T cell compartment containing tumor-specific antigen receptors with high avidity

Project description:T cell receptor (TCR) avidity is assumed to be a major determinant of the spatiotemporal fate and protective capacity of tumor-specific T cells. However, monitoring polyclonal T cell responses with known TCR avidities in vivo over space and time remains challenging. Here, we investigated the fate and functionality of tumor neoantigen-specific T cells with TCRs of distinct avidities in a well-established, reductionist preclinical tumor model and human melanoma patients. Surprisingly, we found that both high- and low-avidity T cells are similarly abundant within the tumor and adopt concordant phenotypic signs of exhaustion. Outside the tumor, high-avidity TCR T cells were also not generally overrepresented, but instead selectively enriched in T cell populations with intermediate PD-1 protein expression or corresponding RNA and surface protein signatures of recent activation. Tumor-reactive TCRs with high protective capacity circulating in peripheral blood are therefore characterized by a signature of recent activation.

2022-06-03 | GSE205145 | GEO

Proteogenomic Discovery of Neoantigens Facilitates Personalized Multi-antigen Targeted T cell Immunotherapy for Brain Tumors

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

Neoantigen-specific stem cell memory-like CD4+ T cells mediate immunotherapy of solid tumors

Project description:The expansion of neoantigen (NeoAg)-specific T cells often accompanies clinical responses to immunotherapies, highlighting the importance of these cells for antitumor immunity. While NeoAg-specific CD8+ T cells have been broadly studied, the role of NeoAg-specific CD4+ T cells is less well understood. To study the antitumor mechanisms of NeoAg-specific CD4+ T cells, we sorted single CD4+ T cells specific for an epitope derived from a mutated clathrin heavy chain gene (CLTCH129>Q) expressed by the murine squamous cell carcinoma VII (SCC VII) tumor. T cell receptor (TCR) sequencing analysis revealed the presence of four distinct TCR clonotypes and expression of these TCRs in primary cells was sufficient to confer preferential recognition of CLTCH129>Q as compared to the corresponding wildtype CLTC epitope. Despite differences in TCR avidity, both moderate and high avidity CD4+ T cells were capable of proliferating to similar levels in response to tumor antigen in vivo and enhancing primary tumor immunity in a CD8+ T cell- and CD40L-dependent manner. Finally, we demonstrate that adoptive cellular therapy (ACT) with T stem cell memory (TSCM)-like CLTCH129>Q-specific CD4+ T cells differentiated ex vivo in culture with IL-7 and IL-15 promotes therapeutic tumor immunity associated with enhanced T cell persistence, maintenance of adoptively transferred TSCM-like cells in the tumor-draining lymph node (tdLN), and activation of CD8+ T cells in the tdLN. Overall, these findings illuminate the mechanistic role of NeoAg-specific CD4+ T cells in tumor immunity, provide insights into the impact of TCR avidity on the helper functions of CD4+ T cells, and highlight the therapeutic potential of ACT with TCR-engineered CD4+ T cells.

2023-05-24 | GSE229221 | GEO

Apoptosis-regulated low avidity cancer-specific CD8+ T cells can be rescued to eliminate HER-2/neu expressing tumors by costimulatory agonists in tolerized mice

Project description:A major barrier of vaccines as cancer treatment is their failure to activate and maintain a complete cancer-specific CD8+ effector T cell repertoire. Low avidity T cells are more likely to escape clonal deletion in the thymus when compared to higher avidity T cells, and therefore comprise the major population of effector T cells available for activation in cancer patients. However, low avidity T cells fail to traffic into the tumor microenvironment and function in eradicating tumor under optimal vaccination conditions as opposed to higher avidity T cells that escape clonal deletion and do function in tumor killing. We utilized high and low avidity TCR transgenic CD8+ T cells specific for the immunodominant epitope of HER-2/neu (RNEU420-429) to identify signaling pathways responsible for the inferior activity of low avidity T cells. Adoptive transfer of these cells into tumor-bearing vaccinated mice identified members of apoptosis pathways as being upregulated in low avidity T cells. The increased expression of pro-apoptotic proteins by low avidity T cells promoted their own cell death and also that of other tumor-specific CD8+ T cells within their local environment. Importantly, this pro-apoptotic effect was overcome using a strong costimulatory signal that prevents activation-induced cell death and enables low avidity T cells to traffic into the tumor and assist in tumor clearance. These findings identify new therapeutic opportunities for activating the most potent anticancer T cell responses. High and low avidity T cells were isolated from TCR transgenic mice and adoptively transferred into Cy-treated, vaccinated, neu-N mice. Three days after adoptive transfer T cells were isolated from the tumor draining nodes and RNA was extracted for gene expression analysis.

2014-01-14 | E-GEOD-54020 | biostudies-arrayexpress

Reprograming responsiveness of tolerogenic CD8+ T cells using a CXCR4 antagonist-armed oncolytic virus requires reversal of M2 macrophage polarization

Project description:Overcoming barriers to the generation of antitumor immunity to self-and neo-antigens is a central concern of cancer immunotherapy. This study investigated the effect of interactions between ovarian cancer (OC) cells and the tumor microenvironment (TME) on the ability of oncolytic virotherapy to activate responsiveness of self antigen-specific and neoantigen-specific CD8+ T lymphocytes in tolerogenic and wild-type (WT) murine tumor models, respectively

2022-06-30 | GSE199880 | GEO

Expression profiling of mouse melanomas with or without UVB-induced neoantigens and after combination immunotherapy

Project description:Syngeneic grafts of the D4M.3A.3 (parental) mouse melanoma cell line (derived from a Tyr::CreER;BrafCA;Ptenlox/lox mouse) in C56BL/6 mice model poorly immunogenic, low neoantigen human melanomas. The D3UV2 (UV2) cell line was derived by serial UVB irradiation and single cell cloning. The addition of UVB-induced putative neoantigens sensitizes UV2 syngeneic melanoma grafts to immune checkpoint inhibitors and triggers epitope skewing to tumor-lineage self-antigens, a phenomenon that can be successfully mimicked in parental melanomas through treatment combinations such as anti-PD-1 with ablative fractional photothermolysis and imiquimod. Our mouse models were used to characterize gene expression changes between neoantigen rich and neoantigen poor melanomas, and with immunotherapy.

2021-02-16 | GSE159344 | GEO

Highly Immunogenic Cancer Cells Require Activation of the WNT Pathway for Immunological Escape

Project description:PD-1 blockade therapy exerts antitumor effects by restoring the infiltration of tumor antigen-specific CD8+ T cells. While neoantigens arising from gene alterations in cancer cells comprise critical tumor antigens in antitumor immunity, a subset of non-small-cell lung cancers (NSCLCs) harboring substantial tumor mutation burden (TMB) lack CD8+ T cells in the tumor microenvironment (TME), resulting in resistance to PD-1 blockade therapy. This resistance is an urgent issue, so the mechanism(s) mediating impaired antitumor immunity in highly mutated NSCLCs need to be explored. Here, we show that activation of the WNT/b-catenin signaling pathway contributes to the development of a noninflamed TME in tumors with high TMB. NSCLCs that lack immune cell infiltration into the TME despite high TMB preferentially upregulate the WNT/b-catenin pathway. Immunological assays revealed that those patients harbored neoantigen-specific CD8+ T cells in the peripheral blood but not in the TME, suggesting impaired T cell infiltration into the TME due to the activation of WNT/b-catenin signaling. In our animal model, the accumulation of gene mutations in cancer cells increased CD8+ T cell infiltration into the TME, slowing tumor growth. However, further accumulation of gene mutations blunted antitumor immunity by excluding CD8+ T cells from tumors in a WNT/b-catenin signaling-dependent manner. Combined treatment with PD-1 blockade and WNT/b-catenin signaling inhibitors induced far stronger antitumor immunity than either treatment alone. We propose a mechanism-oriented combination therapy concept in the cancer immunotherapy field, i.e., the combination of immune checkpoint inhibitors with drugs that target specific molecules in cancer cell-intrinsic oncogenic signaling pathways involved in immune escape.

2021-09-17 | GSE181820 | GEO

RNA-seq of effector (CD43+) CD8+ T cells, CD45+ hematopoietic cells and CD45- tumor/stromal cells from mice bearing bilateral AT-3 tumors following radio-immunotherapy of which one tumor was irradiated

Project description:Radiotherapy (RT) destroys tumor cells, which may lead to release of antigens and immune-activating signals. In this way, RT may act as an in situ vaccine and kick-start a T-cell response against the tumor. Immunotherapy enhances tumor-specific T-cell responses. Combination of radiotherapy and immunotherapy (radio-immunotherapy (RIT)) can therefore be expected to synergize in inducing and sustaining systemic anti-tumor T-cell responses. However, in the clinic, systemic combined responses between radiotherapy and immunotherapy are rarely observed, as the effect of RIT combinations on ‘abscopal’ tumors outside the radiotherapy field are not (yet) greater than the effect of immunotherapy alone. In order to define potential bottlenecks in the tumor micro-environment that impede CD8 T cell activity, we harvested irradiated and non-irradiated tumors from the same mice that were treated with RIT (10 Gy RT, anti-CD137 and anti-PD1). From these tumors, effector (CD43+) CD8 T cells, ‘other’ hematopoietic (CD45+) cells and tumor/stromal (CD45-) were sorted and RNA sequencing was performed to identify differences between these cell populations in the irradiated and non-irradiated tumors that could explain the lack of T cell activity in the non-irradiated tumor.

2019-02-12 | E-MTAB-6914 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data