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Inhibition of PARP14 restores response to α-PD1 immune checkpoint inhibition in tumours with resistance driven by IFNγ. IFNG Study.

ABSTRACT: Inhibition of PARP14 restores response to α-PD1 immune checkpoint inhibition in tumours with resistance driven by IFNγ. IFNG Study.

PROVIDER: PRJEB56191 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR10228800_1.fastq.gz	Fastqsanger.gz
	ERR10228800_2.fastq.gz	Fastqsanger.gz
	ERR10228801_1.fastq.gz	Fastqsanger.gz
	ERR10228801_2.fastq.gz	Fastqsanger.gz
	ERR10228802_1.fastq.gz	Fastqsanger.gz

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Inhibition of PARP14 restores response to α-PD1 immune checkpoint inhibition in tumours with resistance driven by IFNγ. IFNG Study.

Project description:While immune checkpoint blockade therapy (ICBT) benefits cancer patients, many fail to maintain their response due to adaptive resistance mechanisms. IFNγ is critical for cellular immunity, but also promotes adaptive resistance to ICBT. We have established a role for PARP14 in mediating IFNγ-induced adaptive resistance. We confirm that chronic pre-treatment of tumour cells with IFNγ confers resistance to α-PD-1 antibodies in syngeneic mouse tumour models. We identified that PARP14 was consistently upregulated in cancer cells treated chronically with IFNγ as well as in IFNγ-high melanoma samples. Further, we showed that PARP14 knockdown or pharmacological inhibition restores sensitivity to α-PD-1 antibodies accompanied by increased immune cell infiltration into tumours but the decreased presence of regulatory T cells. RNA sequencing analysis of tumours and cultured cells treated with PARP14 inhibitor showed an upregulation of inflammatory-related pathways. In conclusion, PARP14 is an actionable target for reversing IFNγ-driven adaptive resistance to ICBT.

2023-08-22 | E-MTAB-12196 | biostudies-arrayexpress

Inhibition of PARP14 restores response to α-PD1 immune checkpoint inhibition in tumours with resistance driven by IFNγ. PARP14 study.

2023-08-08 | E-MTAB-12195 | biostudies-arrayexpress

Inhibition of PARP14 restores response to α-PD1 immune checkpoint inhibition in tumours with resistance driven by IFNγ. Mouse tumour samples

2023-08-08 | E-MTAB-12194 | biostudies-arrayexpress

Inhibition of PARP14 restores response to α-PD1 immune checkpoint inhibition in tumours with resistance driven by IFNγ. PARP14 study.

Project description:Inhibition of PARP14 restores response to α-PD1 immune checkpoint inhibition in tumours with resistance driven by IFNγ. PARP14 study.

| PRJEB56190 | ENA

Inhibition of PARP14 restores response to α-PD1 immune checkpoint inhibition in tumours with resistance driven by IFNγ. Mouse tumour samples

Project description:Inhibition of PARP14 restores response to α-PD1 immune checkpoint inhibition in tumours with resistance driven by IFNγ. Mouse tumour samples

| PRJEB56188 | ENA

Defined IFNg levels improve anti-tumor and preclinical testing of immunotherapy in hosts with cancer and underlying autoimmunity

Project description:Most immunotherapies benefit only subsets of cancer patients, except those with autoimmune diseases due to dysregulation of their immune system. Here, the ARE-del mouse model featuring IFNg-autoimmunity allowed us to examine the relationship between cancer, autoimmunity and immunotherapy. We demonstrate that systemic levels of IFNg below 20 pg/ml in ARE-del+/- (HET) mice exerts moderate anti-tumor effects and increase (p=0.02; ANOVA) overall survival (OS); while higher levels did not that replicate in vivo the anti-tumor “bell shape” response of IFNg. Having confirmed that PD1 and CD40 are expressed in tumor-bearing ARE-del mice, anti-PD1 and anti-CD40 alone or combined were used to improve the antitumor effects of IFNg in ARE-del+/- (HET) mice. In ARE-del+/+ (WT) mice, PD1/CD40 inhibited tumor growth and improve OS because it prevented increased infiltration and trapping of tumor associated macrophages (TAMs) into necrotic areas, an event also decreased by anti-CD40 but promoted by anti-PD1. Conversely, in ARE-del+/- (HET) mice, MHC class II expressing TAM infiltration associated with severe hematological and liver adverse effects hampered the efficiency of PD1/CD40, despite significant tumor growth inhibition and strong induction of IFNg signaling. Thus, excessive activation of IFN negatively impacted immune outcome. Given the lack of consensus on the right levels of IFNg, our data show the upper limit of IFNg that define the efficacy of checkpoint inhibitors in tumor-bearing hosts with autoimmune disease.

2017-11-25 | GSE90885 | GEO

PARP14 is a Novel Target in STAT6 Mutant Follicular Lymphoma

Project description:The variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (TFH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4/STAT6 target genes in STAT6MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6MUT enhanced IL-4 induced FCER2/CD23, CCL17 and CCL22 expression and was associated with nuclear accumulation of pSTAT6. RNA sequencing identified PARP14 -a transcriptional switch and co-activator of STAT6- among the top differentially upregulated genes in IL-4 stimulated STAT6MUT lymphoma cells and in STAT6MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6MUT but not STAT6WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6MUT FL.

2022-07-17 | GSE208031 | GEO

PD1 completely suppresses the transcriptional response induced by the T cell receptor

Project description:Functional impairment of the immune response to chronic viral infections and malignancies is characterised by exhausted T cells, which do not respond to antigen. The cell surface receptor PD1 has been implicated in the maintenance of T cell exhaustion and is an attractive target for immunomodulatory approaches to the treatment of such conditions. However, the mechanisms by which PD1 signalling causes exhaustion and the exact response of T cells to PD1 activation are not clear although it has been suggested that PD1 up regulates a number of anti-proliferative factors. Here we perform cytokine and transcriptional profiling of uninfected primary human T cells to characterise these events. We find that PD1 completely prevents cytokine and transcrip- tional changes induced by CD3/28 stimulation. We do not see any factors specifically induced by PD1, including BATF or IL10 which have previously been linked to PD1 activity. Together with the work of others this confirms that PD1 is the sole effector of T cell exhaustion and that infection is responsible for BATF and IL10 up regulation. As a consequence future therapeutic strategies will be confined to the inhibition of PD1 and not a downstream effector.

2012-04-01 | E-MEXP-3410 | biostudies-arrayexpress

Long non-coding RNA GRASLND affects melanoma phenotypic switch and modulates immunogenicity by inhibition of the IFNγ signaling pathway (IFNg treatment and GRASLND KD).

Project description:Melanoma is a highly malignant tumor, that stands as the most lethal form of skin cancer and is characterized by notable phenotypic plasticity and intratumoral heterogeneity. Melanoma plasticity is involved in tumor growth, metastasis and therapy resistance. Long non-coding RNAs (lncRNAs) could influence plasticity due to their regulatory function. However, their role and mode of action are poorly studied. Here, we show a relevance of lncRNA GRASLND in melanoma phenotypic switch, IFNγ signaling and immunogenicity. GRASLND knockdown revealed switching towards a dedifferentiated, slow-proliferating and highly-invasive cell state. Interestingly, GRASLND is overexpressed in differentiated melanomas and associated with poor prognosis. Accordingly, we found GRASLND expressed in immunological “cold” tumors and it negatively correlates with gene signatures of immune response activation. In line, silencing of GRASLND under IFNγ enhanced the expression of IFNγ-stimulated genes, including HLA-I antigen presentation, demonstrating suppressive activity of GRASLND on IFNγ signaling. Based on our findings, we hypothesize an adaptive resistance mechanism of melanoma cells evading the immune system via inhibition of IFNγ signaling by GRASLND overexpression and highlight its value as a negative prognostic factor for melanoma.

2024-09-18 | GSE273020 | GEO

miRNA expression between CD4+PD1+ and CD4+PD1- T cells

Project description:Recent success in cancer immunotherapy has come from the blockade of inhibitory receptors on T cells, such as programmed cell death-1, which can induce a state of T cell exhaustion upon constant antigen stimulation. Understanding miRNA regulation of PD1 can be useful to discover miRNAs for use in therapy or as prognostic markers in various diseases including cancer, autoimmunity and transplantation. We used microarrays to discover global miRNA expression changes upon PD1 upregulation and identified miRNAs that are both up- and down-regulated. B16F10 cells were injected subcutaneously into C57BL/6 mice and 16 days later CD4+PD1+ and CD4+PD1- were sorted from the lymph nodes and spleen for RNA extraction and hybridization on Affymetrix miRNA array.

2015-08-01 | E-GEOD-65208 | biostudies-arrayexpress

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