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Expression analysis of CD8+ T cells following high-avidity or low-avidity T cell receptor (TCR) stimulation in the presence or absence of a DOT1L inhibitor

ABSTRACT: Adoptive T cell therapy (ACT) is a promising therapeutic approach for cancer patients. The use of allogeneic T cell grafts will improve its applicability and versatility provided that inherent allogeneic responses are controlled. T cell activation is finely regulated by multiple signaling molecules that are transcriptionally controlled by epigenetic mechanisms. Through extensive chemical probe screening, we found that inhibiting DOT1L, a histone H3-lysine 79 methyltransferase, alleviated allogeneic T cell responses. DOT1L inhibition reduced miR-181a expression, which increased the ERK phosphatase DUSP6 expression. The inhibition of DOT1L or ectopic expression of DUSP6 in T cells prevented the development of graft-versus-host disease while retaining potent antitumor activity in multiple ACT models. These results suggest that DOT1L inhibition may enable the safe and effective use of allogeneic antitumor T cells by suppressing unwanted immunological reactions in ACT. To further explore how DOT1L inhibition differentially affects high- and low-avidity stimulation-mediated T cell responses, gene expression profiles of DMF5- (high affinity) or cl.413- (low affinity) TCR-transduced T cells with or without SGC0946 treatment were analyzed following TCR stimulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE95038 | GEO | 2018/04/20

REPOSITORIES: GEO

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Gene expression analysis of human CD8+ T cells treated with a DOT1L inhibitor

Project description:Adoptive T cell therapy (ACT) is a promising therapeutic approach for cancer patients. The use of allogeneic T cell grafts will improve its applicability and versatility provided that inherent allogeneic responses are controlled. Through extensive chemical probe screening, we found that inhibiting DOT1L, a histone H3-lysine 79 methyltransferase, alleviated allogeneic T cell responses. DOT1L inhibition with SGC0946 selectively ameliorated low-avidity T cell responses but not high-avidity antitumor T cell responses mediated by the high-affinity T cell receptor or chimeric antigen receptor. The inhibition of DOT1L in T cells prevented the development of graft-versus-host disease while retaining potent antitumor activity in xenogeneic ACT models. These results suggest that DOT1L inhibition may enable the safe and effective use of allogeneic antitumor T cells by suppressing unwanted immunological reactions in ACT.

2018-04-20 | GSE108694 | GEO

Antitumor effects of DOT1L inhibition in retinoblastoma

Project description:Antitumor effects of DOT1L inhibition in retinoblastoma

| PRJNA728658 | ENA

Transcription profiling of CD8+ T cells from BM3.3 transgenic mice during responses to TCR ligands of different avidity

Project description:To identify the molecular bases for divergence in differentiation programs of naïve CD8 T cells, we monitored gene expression profile of CD8+ T cells from BM3.3 transgenic mice during responses to TCR ligands of different avidity (full response with antigen presenting cells from C57BL/6 mice , partial response with antigen presenting cells from C57BL/6.C-H-2bm8 mice).

2004-07-07 | E-MEXP-16 | biostudies-arrayexpress

DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression (single-cell RNA-seq)

Project description:Chronic myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed bulk transcriptome profiling accompanied by single cell RNA-sequencing on CD34+ stem/progenitor cells from serial patient samples obtained at the chronic MPN and sAML phases, identifying aberrantly increased expression of dual-specificity phosphatase 6 (DUSP6) underlying disease transformation. Genetic and pharmacologic targeting of DUSP6 led to inhibition of S6 and JAK/STAT signaling, resulting in potent suppression of cell proliferation, while also reducing inflammatory cytokine production in primary samples. Furthermore, ectopic DUSP6 expression augmented proliferation and mediated JAK2 inhibitor resistance, while DUSP6 inhibition reduced colony-forming potential of JAK2 inhibitor-persistent patient cells. Mechanistically, DUSP6 perturbation dampened S6 signaling via inhibition of RSK1, which we identified as a second indispensable candidate associated with poor clinical outcome. Ectopic expression of DUSP6 in patient-derived xenograft (PDX) models exacerbated disease severity and led to early lethality, whereas DUSP6 knockdown suppressed leukemic engraftment. Finally, pharmacological inhibition of DUSP6 potently and specifically suppressed disease development across Jak2 V617F and MPL W515L MPN mouse models, as well as sAML PDXs, without inducing toxicity in healthy controls. These findings underscore DUSP6 in driving disease transformation and therapeutic resistance, and highlight the DUSP6-RSK1 axis as a novel, druggable pathway in myeloid malignancies.

2022-10-25 | GSE214914 | GEO

DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression (RNA-Seq)

2022-10-25 | GSE190517 | GEO

DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression (microarray)

2022-10-25 | GSE214360 | GEO

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

Homo sapiens

Project description:TCR affinity-dependent functional inhibition via PD-1 and SHP-1 phosphatase

| PRJNA183876 | ENA

Peli1-mediated TSC1 ubiquitination site

Project description:Metabolic fitness of T cells is crucial for immune responses against infections and tumorigenesis. Both the T cell receptor (TCR) signal and environmental cues contribute to the induction of T cell metabolic reprogramming, but the underlying mechanism is incompletely understood. Here we identified the E3 ubiquitin ligase Peli1 as an important regulator of T cell metabolism and antitumor immunity. Peli1 ablation profoundly promotes tumor rejection, associated with increased tumor-infiltrating CD4 and CD8 T cells. The Peli1-deficient T cells display markedly stronger metabolic activities, particularly glycolysis, than wildtype T cells. Peli1 controls the activation of a metabolic kinase, mTORC1, stimulated by both the TCR signal and growth factors, and this function of Peli1 is mediated through regulation of the mTORC1-inhibitory proteins, TSC1 and TSC2. Peli1 mediates non-degradative ubiquitination of TSC1, thereby promoting TSC1-TSC2 dimerization and TSC2 stabilization. These results establish Peli1 as an important regulator of T cell metabolism and antitumor immunity and suggest a novel mechanism that controls mTORC1 activation.

2020-11-23 | PXD020734 | Pride

Gene expression analysis in adoptive T cell immunotherapy (ACT)

Project description:To understand the global effector immune responses in the tumor induced by ACT, we performed a gene chip analysis using B16 melanoma-pmel-1 TCR transgenic T cells model. Gene expression was measured in the tumor from untreated or ACT mice on day 1, 3, 5 and 7. Gene expression was also measured in the tumor on day 3, 5 and 7 from ACT mice with anti-IFNg or control Rat IgG antibodies treatment.

2014-08-25 | E-GEOD-57304 | biostudies-arrayexpress

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