Human Immune Exhaustion Gene Expression Profile in C7R-CAR and CAR NK cells
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PROVIDER: PRJNA1162526 | ENA |
REPOSITORIES: ENA
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Project description:The purpose of this experiment was two-fold. The first was to examine how the gene expression profile changes over time in C7R-CAR NK cells. C7R is a constitutively active IL-7 receptor that provides persistent activation of STAT5. The second was to examine the differential gene expression in C7R CAR NK cells or CAR NK treated with exogenous IL-15 (exIL15) after 2 weeks of stimulation.
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Project description:Chimeric antigen receptor (CAR) engineering of NK cells is an active area of research with early-phase clinical studies showing an excellent safety profile with encouraging clinical responses. However, the transcriptional signatures that control the fate of CAR-NK cell after infusion and their association with tumor control remain poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) to depict the evolution of various engineered CAR-NK cells from the ex vivo infusion products to the in vivo peak phase of tumor control and finally to the relapse phase. Single cell RNA sequencing (scRNA) has revolutionized high-thoughout systems-based analysis of cellular and functional heterogeneity, and dynamic changes in the immune response during the anti-tumor immune cell therapy . The goals of this work are to compare transcriptome profiling (RNA-seq) from both engrafted tumor cells and infused CAR-NK cells over time of treatment course to evaluate the kenetic of tumor cell response and effector functional change of CAR-NK cell. Our study represents the first detailed transcriptomic analysis of using CAR-NK cell therapy aganist Raji-engrafted mouse model. Collecting samples from different time points and organs, the data analysis reported here should privide an envision of the dynamic about how tumor response to immune cell therapy of using CAR-NK cells and also how immune effector fucntion of CAR-NK cell was modulated over time during the treatment courses.
2022-05-25 | GSE190976 | GEO
Project description:Primary chimeric antigen receptor (CAR) natural killer (NK) cells show strong cytotoxic efficacy against acute myeloid leukemia (AML) in vivo. However, NK cell-mediated tumor killing is often impaired by tumor-mediated immune cell inactivation. Here, we report a novel strategy to overcome NK cell inhibition caused by the immune checkpoint NKG2A, which interacts with HLA-E expressed on AML blasts. We generated AML-specific CD33-directed CAR (CAR33)-KLRC1ko-NK cells with CRISPR/Cas9-based gene editing of the NKG2A-encoding KLRC1 gene. Single-cell multi-omic analyses revealed a higher proportion of activated cells in CAR33-NK- and CAR33-KLRC1ko-NK pools, which were preserved following AML-cell contact. This activated state of the CAR33-KLRC1ko-NK cells has been translated into improved antileukemic activity in vitro and in vivo against AML cell lines and primary blasts. This dual modification of primary NK cells has the potential to bypass the suppressive effect not only of AML but also in a broad range of other cancer identities.
2024-07-16 | GSE221552 | GEO
Project description:Dysfunction in T cells limits the efficacy of cancer immunotherapy. We profiled the epigenome, transcriptome, and enhancer connectome of exhaustion-prone GD2-targeting HA-28z chimeric antigen receptor (CAR) T cells and control CD19-targeting CAR T cells, which present less exhaustion-inducing tonic signaling, at multiple points during their ex vivo expansion. We found widespread, dynamic changes in chromatin accessibility and 3D chromosome conformation preceding changes in gene expression, notably at loci proximal to exhaustion-associated genes such as PDCD1, CTLA4, and HAVCR2, and increased DNA motif access for AP-1 family transcription factors, which are known to promote exhaustion. Although T cell exhaustion has been studied in detail in mouse, we find that the regulatory networks of T cell exhaustion differ between the species and involve distinct loci of accessible chromatin and cis-regulated target genes in human CAR T cell exhaustion. Deletion of exhaustion-specific candidate enhancers of PDCD1 suppress the expression of PD-1 in an in vitro model of T cell dysfunction and in HA-28z CAR T cells, suggesting enhancer editing as a path forward in improving cancer immunotherapy.
2021-05-01 | GSE168881 | GEO
Project description:Dysfunction in T cells limits the efficacy of cancer immunotherapy. We profiled the epigenome, transcriptome, and enhancer connectome of exhaustion-prone GD2-targeting HA-28z chimeric antigen receptor (CAR) T cells and control CD19-targeting CAR T cells, which present less exhaustion-inducing tonic signaling, at multiple points during their ex vivo expansion. We found widespread, dynamic changes in chromatin accessibility and 3D chromosome conformation preceding changes in gene expression, notably at loci proximal to exhaustion-associated genes such as PDCD1, CTLA4, and HAVCR2, and increased DNA motif access for AP-1 family transcription factors, which are known to promote exhaustion. Although T cell exhaustion has been studied in detail in mouse, we find that the regulatory networks of T cell exhaustion differ between the species and involve distinct loci of accessible chromatin and cis-regulated target genes in human CAR T cell exhaustion. Deletion of exhaustion-specific candidate enhancers of PDCD1 suppress the expression of PD-1 in an in vitro model of T cell dysfunction and in HA-28z CAR T cells, suggesting enhancer editing as a path forward in improving cancer immunotherapy.
2021-05-01 | GSE168880 | GEO
Project description:We performed transcriptome sequencing on Neo-2/15 stimulated CAR NK cells,to shed light on the function and phenotype changes of CAR-NK cells stimulated by IL-2 and Neo-2/15.
2023-12-31 | GSE243530 | GEO
Project description:CAR T cells mediate antitumor effects in a small subset of cancer patients, but dysfunction due to T cell exhaustion is an important barrier to progress. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system employing a tonically signaling CAR, which induces hallmarks of exhaustion described in other settings. Exhaustion was associated with a profound defect in IL-2 production alongside increased chromatin accessibility of AP-1 transcription factor motifs, and overexpression of numerous bZIP and IRF transcription factors that have been implicated in inhibitory activity. Here we demonstrate that engineering CAR T cells to overexpress c-Jun, a canonical AP-1 factor, enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved antitumor potency in numerous in vivo tumor models. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells and that engineering CAR T cells to overexpress c-Jun renders them exhaustion-resistant, thereby addressing a major barrier to progress for this emerging class of therapeutics.
2019-10-01 | GSE136891 | GEO
Project description:CAR T cells mediate antitumor effects in a small subset of cancer patients, but dysfunction due to T cell exhaustion is an important barrier to progress. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system employing a tonically signaling CAR, which induces hallmarks of exhaustion described in other settings. Exhaustion was associated with a profound defect in IL-2 production alongside increased chromatin accessibility of AP-1 transcription factor motifs, and overexpression of numerous bZIP and IRF transcription factors that have been implicated in inhibitory activity. Here we demonstrate that engineering CAR T cells to overexpress c-Jun, a canonical AP-1 factor, enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved antitumor potency in numerous in vivo tumor models. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells and that engineering CAR T cells to overexpress c-Jun renders them exhaustion-resistant, thereby addressing a major barrier to progress for this emerging class of therapeutics.
2019-10-01 | GSE136853 | GEO
Project description:CAR T cells mediate antitumor effects in a small subset of cancer patients, but dysfunction due to T cell exhaustion is an important barrier to progress. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system employing a tonically signaling CAR, which induces hallmarks of exhaustion described in other settings. Exhaustion was associated with a profound defect in IL-2 production alongside increased chromatin accessibility of AP-1 transcription factor motifs, and overexpression of numerous bZIP and IRF transcription factors that have been implicated in inhibitory activity. Here we demonstrate that engineering CAR T cells to overexpress c-Jun, a canonical AP-1 factor, enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved antitumor potency in numerous in vivo tumor models. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells and that engineering CAR T cells to overexpress c-Jun renders them exhaustion-resistant, thereby addressing a major barrier to progress for this emerging class of therapeutics.
2019-10-01 | GSE136796 | GEO