Neoantigen-Specific CD8 T Cells with High Structural Avidity Preferentially Reside in and Eliminate Tumors
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ABSTRACT:
PROVIDER: PRJNA971992 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24529636.fastq.gz | Fastqsanger.gz | |||
| SRR24529637_1.fastq.gz | Fastqsanger.gz | |||
| SRR24529637_2.fastq.gz | Fastqsanger.gz | |||
| SRR24529638_1.fastq.gz | Fastqsanger.gz | |||
| SRR24529638_2.fastq.gz | Fastqsanger.gz |
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Project description:Neoantigen-Specific CD8 T Cells with High Structural Avidity Preferentially Reside in and Eliminate Tumors (VDJ)
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Project description:Neoantigen-Specific CD8 T Cells with High Structural Avidity Preferentially Reside in and Eliminate Tumors (GEX)
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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:This SuperSeries is composed of the SubSeries listed below.
2023-05-18 | GSE232447 | GEO
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
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.
2014-01-14 | GSE54020 | GEO
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
Project description:The avidity of the T-cell receptor (TCR) for antigenic peptides presented by the MHC (pMHC) on cells is an essential parameter for efficient T cell-mediated immunity. Yet, whether the TCR-ligand avidity can drive the clonal evolution of virus antigen-specific CD8 T cells, and how this process is determined in latent Cytomegalovirus (CMV)- against Epstein-Barr virus (EBV)-mediated infection remains largely unknown. Here, we quantified monomeric TCR-pMHC dissociation rates on CMV- and EBV-specific individual TCR-alpha-beta clonotypes and polyclonal CD8 T cell populations in healthy donors over a follow-up time of 15-18 years. Within CMV/pp65-specific T cell repertoires, a progressive contraction of clonotypes with high TCR-pMHC avidity and low CD8 binding dependency was observed, leading to an overall avidity decline during long-term antigen exposure. We identified a unique transcriptional signature preferentially expressed by high-avidity CMV/pp65-specific T cell clonotypes, including the inhibitory receptor LILRB1. Interestingly, T cell clonotypes of high-avidity showed higher LILRB1 expression than the low-avidity ones and LILRB1 blockade moderately increased T cell proliferation. Similar findings were made for CD8 T cell repertoires specific for the CMV/IE-1 epitope. There was a gradual in vivo loss of high-avidity T cells with time for both CMV specificities, corresponding to virus-specific CD8 T cells expressing enhanced LILRB1 levels. In sharp contrast, the EBV/BMFL1-specific T cell clonal composition and distribution, once established, displayed an exceptional stability, unrelated to TCR-pMHC binding avidity or LILRB1 expression. Together, these findings reveal an overall long-term avidity decline of CMV- but not EBV-specific T cell clonal repertoires, highlighting the differing role played by TCR-ligand avidity over the course of these two latent herpesvirus infections. Our data suggest that the inhibitor receptor LILRB1 potentially restricts the clonal expansion of high-avidity CMV-specific T cell clonotypes during latent infection. We propose that the mechanisms regulating the long-term outcome of CMV- and EBV-specific memory CD8 T cell clonotypes in humans are distinct.
2023-11-15 | GSE246111 | GEO
Project description:CD8 T cells which recognize neoepitopes are central to immune control of cancers. T cells, through T cell receptors, recognize neoepitope peptide-MHC I on cancer cells. The strength (or avidity) of the T cell receptor- peptide-MHCI interaction is a critical variable in immune control of cancers in vivo. Here, analyzing neoepitope-specific CD8 cells of distinct avidities to validated neoepitopes of a mouse tumor, low avidity T cells are observed to be the sole mediators of cancer control in vivo. Low avidity cells are also observed to be solely responsive to checkpoint blockade in mice and in humans. High avidity T cells are not only ineffective but suppress immune response. The mechanistic basis of the differences in the anti-tumor activity of cells of low and high avidities, lies in the higher exhaustion status of high avidity cells. High avidity T cells have a distinct transcriptomic profile which creates an Avidity Score, used here to identify in silico, the low and high avidity T cell populations in mice and humans. Surprisingly, CD8 T cells with identical TCRs exhibit a wide variation in avidities, suggesting a novel level of regulation of T cell activity. These observations, and the mechanisms that underlie them, shed new light on the endogenous T cell response to cancer and suggest new avenues in cancer immunotherapy.
2024-12-25 | GSE282069 | GEO