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Transcriptional signature of Th17 cells expressing ICOS-based CARs

ABSTRACT: Analysis of TH17 cells redirected with chimeric antigen receptors (CAR) expressing various signaling domains (including CD28, 4-1BB and ICOS) after surrogate antigen stimulation. Our results showed that T cells redirected with an ICOS-based CAR specifically retained a genotype of TH17 cells with expression of Il17a, Il17f, Il1r1, Ccl20, Rorc, and in the absence of Foxp3 CAR-redirected TH17 cells from three different human normal donors were stimulated with immobilized recombinant mesothelin. Gene expression levels were determined prior to stimulation (day 0) and 4, 8, 24 and 96 hours upon antigen recognition.

ORGANISM(S): Homo sapiens

SUBMITTER: Carl June

PROVIDER: E-GEOD-58867 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcriptional signature of Th17 cells expressing ICOS-based CARs

Project description:Analysis of TH17 cells redirected with chimeric antigen receptors (CAR) expressing various signaling domains (including CD28, 4-1BB and ICOS) after surrogate antigen stimulation. Our results showed that T cells redirected with an ICOS-based CAR specifically retained a genotype of TH17 cells with expression of Il17a, Il17f, Il1r1, Ccl20, Rorc, and in the absence of Foxp3

2014-06-26 | GSE58867 | GEO

Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability

Project description:Chimeric antigen receptor–T (CAR-T) cell therapies can eliminate relapsed and refractory tumors, but the durability of antitumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, and influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and changing this asparagine to phenylalanine (CD28-YMFM) promoted durable antitumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing toward Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and antitumor activity. This finding suggests modifications to the costimulatory domains of CAR-T cells can enable longer persistence and thereby improve antitumor response.

2020-02-11 | GSE145007 | GEO

Gene expression of T follicular helper (TFH) cells 6 h after ICOS-L blockade

2015-01-19 | GSE49314 | GEO

Gene expression of T follicular helper (TFH) cells 6 h after ICOS-L blockade

Project description:The maintenance of the TFH phenotype depends on continuous signals via ICOS. For a global assessment of differences in gene expression after interruption of the ICOS pathway a genome wide transcriptome analysis was performed. We used the OT-II adoptive transfer system to isolate antigen-specific TFH cells (day 6 after immunization) after short-term (6 hours) blockade of the ICOS pathway using a monoclonal antibody against ICOS-L. Gene expression profiles of TFH cells with or without ICOS-L blockade. Affymetrix MG 430 2.0 whole genome arrays were performed in duplicates for the control and blockade group (4 arrays in total). To obtain genes significantly regulated upon ICOS L blockade, the expression profiles of TFH cells treated with an isotype control or anti-ICOS-L antibody were compared to each other. After total RNA extraction, reverse transcription, cDNA extraction, the biotinylated cRNA was transcribed, fragmented, and 15 M-BM-5g cRNA hybridized in duplicates for each of the two groups to the 4 GeneChip arrays: Group1 TFH cells control, Group2 TFH cells ICOS-L blockade.

2015-01-19 | E-GEOD-49314 | biostudies-arrayexpress

Gene expression comparison between the murine T-cell hybridoma 6-13-64 ICOS(-) population and ICOS(+) population

Project description:ICOS (Inducible Costimulator) is a T cell costimulatory molecule. We found that the cloned T-cell hybridoma 6-13-64 consists of two populations, ICOS expressing and non-expressing. The aim of this study is to screen for candidate genes that regulate ICOS gene expression by transcriptional profiling and comparison of the ICOS-positive and ICOS-negative subpopulations isolated from the 6-13-64 T-cell hybridoma. One-condition experiment, ICOS(-) vs. ICOS(+) cells. Independently grown and harvested. One replicate per array.

2012-03-31 | E-GEOD-20922 | biostudies-arrayexpress

Expression data from chimeric antigen receptor transduced (CAR) human CD4+ T cells during expansion

Project description:In this data set we include expression data from human CD4+ T cells isolated on day 0, 6, 11 and 24 follow anti-CD3/anti-CD28 magnetic bead stimulation and chimeric antigen receptor transduction. 30 samples were submitted. Samples represented three biological replicates of normal donors transduced with various CARs. CARs used were a cMet 28z specific CAR comprised of the IgG4 hinge, CD28 transmembrane and CD28 and CD3zeta intracellular domains. A CD19 CD28 CAR was specific to CD19, and was comprised of a CD8a hinge, CD28 transmembrane and CD28 and CD3zeta intracellular domain. A third CAR, the CD19 BBz, was used that was specific to CD19 was comprised of a CD8a hinge, CD8a transmembrane and 4-1BB and CD3zeta intracellular domains. Expression data was analyzied on day 0, 6, 11 and 24.

2015-01-14 | E-GEOD-64914 | biostudies-arrayexpress

Gene expression comparison between the murine T-cell hybridoma 6-13-64 ICOS(-) population and ICOS(+) population

2012-04-01 | GSE20922 | GEO

IL12 integrated into the CAR exodomain converts CD8+ T cells to poly-functional NK-like cells with superior killing of antigen-loss tumors

Project description:Chimeric antigen receptor (CAR)-redirected T cell therapy often fails to control tumors in the long-term due to selecting cancer cells that down-regulated or lost CAR targeted antigen. To reprogram the functional capacities of CAR T cells, we inserted IL12 into the extracellular moiety of a CD28- CAR; both the CAR and IL12 were functional indicated by antigen-redirected activation and STAT4 phosphorylation, respectively. CD8+ T cells engineered with a IL12-CAR gained a so far not recognized NK cell-like RNA expression signature and a CD94+CD56+CD62Lhigh phenotype closely similar, but not identical, to NK and cytokine activated killer (CIK) cells. IL12-CAR T cells with specificity for CEA additionally acquired antigen-independent, HLA-E restricted cytotoxicity eliminating both CEA-negative and CEA-positive cancer cells in an antigen-dependent and independent fashion that was in contrast to conventional CEA CAR T cells. Simultaneous signaling through CD3 of the CAR and through IL12 were required and sufficient for inducing NK-like cytotoxicity. Overall, we present a prototype of a new family of CARs that harbor a cytokine integrated into the extracellular module in order to reprogram the functional capacities of CAR T cells towards augmented tumor recognition and elimination.

2021-08-24 | GSE182623 | GEO

Impaired T-cell function in patients with novel ICOS

Project description:Interaction of ICOS - ICOS ligand is required for the germinal center formation, T-cell immune responses, and development of autoimmune diseases. Human ICOS deficiency with the identical ICOS mutation has been identified in nine patients worldwide. In vitro studies showed T-cell defect of the patients was mild, and in vivo autoimmunity was uncommon and mild. Here we report in-depth analysis of T-cell function in two siblings with novel ICOS deficiency. While the brother displayed mild skin infections, psoriasis-like skin region, and defective immunoglobulin class switching, the sister had more severe symptoms, which included immunodeficiency, rheumatoid arthritis, inflammatory bowel disease, interstitial pneumonitis, and psoriasis. Despite of normal CD3/CD28-induced proliferation and IL-2 production in vitro, peripheral blood T-cells from both patients demonstrated decreased percentage of CD4 central and effector memory T-cells and impaired production of Th1, Th2, and Th17 cytokines upon CD3/CD28 costimulation or upon PMA/ionophore stimulation. The defective polarization into effector cells were associated with impaired induction of T-bet, GATA3 and MAF and RORC. Reduced CTLA-4+CD45RO+ FoxP3+ regulatory T-cells and diminished induction of inhibitory cell surface molecules including CTLA-4 were also observed in the patients. Further analysis of the gene expression and immune functions of the patients demonstrated increased induction of RANKL, lack of IFN-g response, and loss of Itch expression upon activation in the female case with autoimmunity. Our study suggests extensive T-cell dysfunction and loss of balance between effector cells and regulatory cells in the ICOS-deficient patients may account for their immunodeficiency and/or autoimmune disorder.

2008-09-26 | GSE12875 | GEO

ICOS costimulation is indispensable for the differentiation of T follicular regulatory cells

Project description:ICOS is a T cell costimulatory receptor critical for Tfh cell generation and function. However, the role of ICOS in Tfr cell differentiation remains unclear. Using Foxp3-Cre-mediated ICOS knockout (ICOS FC) mice, we show that ICOS deficiency in Treg-lineage cells drastically reduces the number of Tfr cells during GC reactions but has a minimal impact on conventional Treg cells. Single-cell transcriptome analysis of Foxp3+ cells at an early stage of the GC reaction suggests that ICOS normally inhibits Klf2 expression to promote follicular features including Bcl6 upregulation. Further, ICOS costimulation promotes nuclear localization of NFAT2, a known driver of CXCR5 expression. Notably, ICOS FC mice had an unaltered overall GC B cell output but showed signs of expanded autoreactive B cells along with elevated autoantibody titers. Thus, our study demonstrates that ICOS costimulation is critical for Tfr cell differentiation and highlights the importance of Tfr cells in maintaining humoral immune tolerance during GC reactions.

2023-02-02 | GSE164995 | GEO

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