CD8+ TILs in NSCLC differentiate into TEMRA via a bifurcated trajectory, deciphering immunogenicity of tumor-antigens
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PROVIDER: PRJNA762913 | ENA |
REPOSITORIES: ENA
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Project description:CD8+ tumor-infiltrating lymphocytes (TILs) comprise phenotypically and functionally heterogeneous subpopulations. Of these, effector memory CD45RA-expressing CD8+ T cells (Temra) have been discovered and characterized as the most terminally differentiated subset. However, their exact ontogeny and physiological importance in association with tumor progression remain poorly understood. We analyzed primary tumors and peripheral blood samples from 26 patients with non-small cell lung cancer and analyzed their phenotypes and functional characteristics using flow cytometry, RNA-sequencing, and bioinformatics. We found that tumor-infiltrating Temra (tilTemra) cells largely differ from peripheral blood Temra (pTemra), with distinct transcriptomes and functional properties. Notably, although majority of the pTemra was CD27-CD28- double-negative (DN), a large fraction of tilTemra population was CD27+CD28+ double-positive (DP), a characteristic of early-stage, less differentiated effector cells. Trajectory analysis revealed that CD8+ TILs undergo a divergent sequence of events for differentiation into either DP or DN tilTemra. Such a differentiation toward DP tilTemra relied on persistent expression of CD27 and CD28 and was associated with weak T cell receptor engagement. Thus, a higher proportion of DP Temra was correlated with lower immunogenicity of tumor antigens and consequently lower accumulation of CD8+ TILs. These data suggest a complex interplay between CD8+ T cells and tumors and define DP Temra as a unique subset of tumor-specific CD8+ TILs that are produced in patients with relatively low immunogenic cancer types, predicting immunogenicity of tumor antigens and CD8+ TIL counts, a reliable biomarker for successful cancer immunotherapy.
2021-09-14 | GSE184053 | GEO
Project description:Memory T cells are heterogeneous in terms of their phenotype and functional properties. We investigated the molecular profiles of human CD8 naïve (TN), central memory (TCM), effector memory (TEM), and effector memory RA (TEMRA) T cells using gene expression microarrays and phospho-protein-specific intracellular flow cytometry. We demonstrate that TCM have a gene expression and cytokine signaling signature that lies between that of TN and TEM or TEMRA cells, whereas TEM and TEMRA are closely related. Our data define the molecular basis for the different functional properties of central and effector memory subsets. We show that TEM and TEMRA cells strongly express genes with known importance in CD8 T cell effector function. In contrast, TCM are characterized by high basal and cytokine-induced STAT5 phosphorylation, reflecting their capacity for self-renewal. Altogether, our results distinguish TCM and TEM/TEMRA at the molecular level and are consistent with the concept that TCM represent memory stem cells.
2005-01-01 | E-TABM-40 | biostudies-arrayexpress
Project description:The majority (60-97%) of KIR3DL3+ CD8 T cells belongs to TEMRA. To understand the function and characteristic of KIR3DL3+ CD8 T cells, we performed RNA-seq of KIR3DL3+ and KIR3DL3- CD8 TEMRA cells
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Project description:Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which neuroinflammation plays a critical function. Recurring viral infections and loss of immune competence increase risk for developing AD, yet the cellular and molecular mechanisms driving these immune changes are unknown. Here we performed mass cytometry of peripheral blood mononuclear cells and detected an immunologic signature of AD characterized by increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. CD8+ TEMRA cells were negatively associated with cognition and single cell RNA sequencing revealed their cytotoxic effector function. Strikingly, we discovered identical, shared T cell receptors (TCRs) of clonally expanded CD8+ TEMRA cells in cerebrospinal fluid (CSF) of three AD patients. Deep TCR sequencing, machine learning, and peptide screens identified the HLA-B*08:01-restricted Epstein-Barr virus trans-activator protein BZLF1 as the cognate antigen of a novel AD CSF TCR . These results provide the first evidence of clonal, antigen-specific T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration
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Project description:Transcriptomic profile of sorted CD8+ TILs from Rag1-/- mice 4 days after transferred. Each group has two replicates.
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Project description:As humans age their memory T cell compartment expands due to lifelong exposure to antigens. This expansion is characterized by the presence of terminally differentiated CD8+ T cells (Temra) which possess an NK cell-like phenotype and are associated with chronic inflammatory conditions. Temra cells are predominantly driven by sporadic cytomegalovirus reactivation (CMV) yet their cellular heterogeneity remains understudied. To address this gap we measured their gene expression profiles and conducted single-cell transcriptome analysis. We show that CD8+ Temra cells are highly heterogeneous and describe subsets specific to old age and CMV infection.
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Project description:Purpose: Transcriptome profiling (RNA-seq) was used to compare the expression differences between T in PBMC and TILs Methods:Paired TILs and T in PBMC cells were sorted from fresh patient blood and tumor samples. Then the mRNA were sequeced using xTen platform. The sequence reads that passed quality filters were analyzed. Results: by extract mRNA from tumor infiltrated T cells from ovarian cancer patient sample and T cells from patient bllod samples, we compared the different expressed genes from TIL and T in blood. Hierarchical clustering of differentially expressed genes uncovered several as yet uncharacterized genes that may contribute to T cell exhausetion. Conclusions: We conclude that T in PBMC and TILs share different transcriptome characterization.
2022-12-18 | GSE157936 | GEO
Project description:RNAseq of 3 CD8 subsets (NAIVE, TEMRA and EM) from 8 paired Healthy Volunteers
2020-05-06 | GSE129356 | GEO
Project description:Highly immunogenic exotoxins were proved to be efficient in improving the immunogenicity of polysaccharides, traditionally known as carrier proteins. However, the efficacy of exotoxins on protein antigens remains to be excluded. In the current study, the candidate antigen PA0833 from Pseudomonas aeruginosa was fused to the α-hemolysin mutant HlaH35A from Staphylococcus aureus. After immunization with the fusion protein, increased titers of PA0833-specific antibodies and higher protective efficacy were observed, companied with decreased bacterial burden and pro-inflammatory cytokines secretion when compared with PA0833 immunization alone. Then, by using fluorescently labeled antigens to track antigen uptake and delivery, we found that fusion to HlaH35A significantly improved antigen uptake in injected muscles and antigen delivery to draining lymph nodes. Both in vivo and in vitro studies demonstrated that increased antigen uptake by fusion to HlaH35A were mainly mediated by monocytes and macrophages in a macropinocytosis dependent manner, probably due to targeting ADAM10, the host receptor of Hla. Further, transcriptome analysis was performed and the result showed that several immune signaling pathways were activated by HPF, which also shed light on the mechanism of improved immunogenicity. Finally, improvement of immunogenicity by fusion to HlaH35A was also confirmed in two other anigens, GlnH from Klebsiella pneumoniae and the model antigen OVA, which indicated that HlaH35A could serve as a universal carrier protein to improve the immunogenicity of protein antigens.
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Project description:It has been shown that tumor infiltrating immune cells have a profound impact on the outcome of FL. To find mechanisms whereby TILs are altered gene expession analysis of highly pure TILs were performed. The study is composed of 4 groups, FL CD4 (n=12), FL CD8 (n=9), Tonsil CD4 (n=7) and Tonsil CD8 (n=7). All FL patients were treatment naive. Cells were flowsorted from cryopreserved single cell suspensions and purity of cells were at least 95%.
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