Rescue of T cell exhaustion by ingenol mebutate
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ABSTRACT:
PROVIDER: PRJNA540148 | ENA |
REPOSITORIES: ENA
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Project description:Inhibitory receptors (IR) and inhibitory ligands function as critical regulators of immune responses by tempering T cell activity to microbial infections and cancers. In humans, several types of persisting viruses such as HIV, HBV and HCV, as well as cancers exploit IR signaling by upregulating IR ligands, resulting in suppression of T cell function (i.e., exhaustion). This allows escape from immune surveillance and continuation of disease. By screening a collection of bioactive small molecules, we identified and validated compounds that restore cytokine production and enhance proliferation of exhausted T cells. Analysis of our top hit ingenol mebutate, a protein kinase C inducing diterpene ester, revealed a role for this molecule in overriding the suppressive signaling cascade mediated by IR signaling on T cells.
2019-12-03 | GSE130406 | GEO
Project description:Actinic keratosis is a common skin disease that may progress to invasive squamous cell carcinoma. Ingenol mebutate has demonstrated efficacy in field treatment of actinic keratosis. However, molecular mechanisms on ingenol mebutate response are not yet fully understood.
2020-05-18 | GSE142108 | GEO
Project description:We studied the transcriptomic profile of actinic keratosis (AK) skin compared to matched samples from uninvolved skin (US) before and after treatment with ingenol mebutate gel. We found that AK has a distinct mRNA profile that separates it from uninvolved skin. In particular, numerous genes associated with epidermal development and keratinocyte differentiation, such as LCE3D, SPRR1A, PI3 and several genes in the keratin family were highly expressed in AK0 skin, but not in US0, in line with the hyperkeratosis characteristic for AK. Topical application of ingenol mebutate had a profound effect on the gene expression profile, and interestingly, many more genes were affected in US than in AK. Enrichment analysis revealed that the main responses to ingenol mebutate treatment of both US and AK were inflammatory response, response to wounding, and wound healing. 30 skin biopsies were analysed; 5 from each of 6 AK patients. Before initiation of treatment, baseline biopsies were taken from one AK lesion (AK0) and from uninvolved skin (US0). A third biopsy was taken after day 1 application of ingenol mebutate from one AK lesion (AK1). The fourth and fifth biopsies were obtained one day after the second topical application with ingenol mebutate from an AK lesion (AK2) and from uninvolved skin (US2), respectively.
2016-03-31 | E-GEOD-63107 | biostudies-arrayexpress
Project description:We studied the transcriptomic profile of actinic keratosis (AK) skin compared to matched samples from uninvolved skin (US) before and after treatment with ingenol mebutate gel. We found that AK has a distinct mRNA profile that separates it from uninvolved skin. In particular, numerous genes associated with epidermal development and keratinocyte differentiation, such as LCE3D, SPRR1A, PI3 and several genes in the keratin family were highly expressed in AK0 skin, but not in US0, in line with the hyperkeratosis characteristic for AK. Topical application of ingenol mebutate had a profound effect on the gene expression profile, and interestingly, many more genes were affected in US than in AK. Enrichment analysis revealed that the main responses to ingenol mebutate treatment of both US and AK were inflammatory response, response to wounding, and wound healing.
2016-03-31 | GSE63107 | GEO
Project description:During persistent antigen stimulation, CD8+ cytolytic T cells (CTL) show a gradual decrease in effector function, or “exhaustion”, which impairs the immune response to tumors and infections. Here we show that NFAT, a transcription factor with an established role in T cell activation, in parallel controls a second transcriptional program conferring the characteristic features of CD8+ T cell exhaustion, including upregulation of genes encoding inhibitory cell surface receptors and diminished TCR signaling. Expression of an engineered NFAT1, which induces this negative regulatory program in the absence of the effector program, interferes with the ability of CD8+ T cells to protect against Listeria infection or attenuate tumor growth in vivo. NFAT elicits this second program of gene expression in large part by binding to a subset of the sites occupied by NFAT during a typical effector response, suggesting that a balance between the two pathways determines the outcome of TCR signaling. Determination of NFAT1 binding sites in CD8 T cells in vitro
2015-02-13 | E-GEOD-64407 | biostudies-arrayexpress
Project description:Differential gene expression after ingenol mebutate (IM) treatment
| PRJNA267521 | ENA
Project description:STING gain-of-function (GOF) mutations lead to T cell lymphopenia, in the context of severe combined immunodeficiency (SCID) for STING GOF V154M mice. This T cell lymphopenia, which is of central origin, has been described as type I IFN independent and associated with dysfunctions of the rare mature T cells found in the periphery. To better describe the biological mechanisms of these dysfunctions, we performed a transcriptomic analysis by RNA-seq on sorted splenic CD4+ and CD8+ mature T cells from STING GOF mice. We highlighted an unexpected T cell exhaustion phenotype that could partly explain their dysfunctions. Acquired very early in life, but only once the peripheral environment is reached, the phenotype appeared to depend neither on type I IFNs, nor on the intrinsic activation of STING in T or stromal cells. Mechanistically, the few mature T cells reaching the periphery seem to be rapidly impacted by the lymphopenic environment through increased antigenic and IL-7 stimulations that could lead to their exhaustion. By using STING GOF long term-hematopoietic stem cells (LT-HSC) transplantations with supportive wild-type bone marrow (BM) cells, we prevented the T cell exhaustion of STING GOF T cells in the resulting non lymphopenic context. With the support of lymphopenic RAG1 hypomorphic mice developing the phenotype, our data uncover a lymphopenia-mediated T cell exhaustion mechanism in STING GOF mice, for which a synergistic effect of the mutation is also envisaged.
2024-01-07 | E-MTAB-13658 | biostudies-arrayexpress
Project description:During persistent antigen stimulation, CD8+ cytolytic T cells (CTL) show a gradual decrease in effector function, or “exhaustion”, which impairs the immune response to tumors and infections. Here we show that NFAT, a transcription factor with an established role in T cell activation, in parallel controls a second transcriptional program conferring the characteristic features of CD8+ T cell exhaustion, including upregulation of genes encoding inhibitory cell surface receptors and diminished TCR signaling. Expression of an engineered NFAT1, which induces this negative regulatory program in the absence of the effector program, interferes with the ability of CD8+ T cells to protect against Listeria infection or attenuate tumor growth in vivo. NFAT elicits this second program of gene expression in large part by binding to a subset of the sites occupied by NFAT during a typical effector response, suggesting that a balance between the two pathways determines the outcome of TCR signaling. Understanding the role of CA-RIT-NFAT1 in T cells
2015-02-13 | E-GEOD-64408 | biostudies-arrayexpress
Project description:T cell exhaustion is a progressive loss of effector function and memory potential due to persistent antigen exposure, which occurs in chronic viral infections and cancer. Here we investigate the relation between gene expression and chromatin accessibility in CD8+ tumor-infiltrating lymphocytes (TIL) that recognize a model tumor antigen and have features of both activation and functional exhaustion. By filtering out accessible regions observed in bystander, non-exhausted, TIL and in acutely restimulated CD8+ T cells, we define a pattern of chromatin accessibility specific for T cell exhaustion, characterized by enrichment for consensus binding motifs for Nr4a and NFAT transcription factors. Anti-PD-L1 treatment of tumor-bearing mice results in cessation of tumor growth and partial rescue of cytokine production by the dysfunctional TIL, with only limited changes in gene expression and chromatin accessibility. Our studies provide a valuable resource for the molecular understanding of T cell exhaustion in cancer and other inflammatory settings.
2017-02-28 | GSE93013 | GEO
Project description:T cell exhaustion is a progressive loss of effector function and memory potential due to persistent antigen exposure, which occurs in chronic viral infections and cancer. Here we investigate the relation between gene expression and chromatin accessibility in CD8+ tumor-infiltrating lymphocytes (TIL) that recognize a model tumor antigen and have features of both activation and functional exhaustion. By filtering out accessible regions observed in bystander, non-exhausted, TIL and in acutely restimulated CD8+ T cells, we define a pattern of chromatin accessibility specific for T cell exhaustion, characterized by enrichment for consensus binding motifs for Nr4a and NFAT transcription factors. Anti-PD-L1 treatment of tumor-bearing mice results in cessation of tumor growth and partial rescue of cytokine production by the dysfunctional TIL, with only limited changes in gene expression and chromatin accessibility. Our studies provide a valuable resource for the molecular understanding of T cell exhaustion in cancer and other inflammatory settings.
2017-02-28 | GSE93001 | GEO