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Translation control of the immune checkpoint in cancer and its therapeutic targeting

ABSTRACT: Translation control of the immune checkpoint in cancer and its therapeutic targeting

PROVIDER: PRJNA414959 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6189660.fastq.gz	Fastqsanger.gz
	SRR6189661.fastq.gz	Fastqsanger.gz
	SRR6189662.fastq.gz	Fastqsanger.gz
	SRR6189663.fastq.gz	Fastqsanger.gz
	SRR6189654.fastq.gz	Fastqsanger.gz

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Translation control of the immune checkpoint in cancer and its therapeutic targeting

Project description:Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly achieved remains largely unresolved. Here, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show that MYC overexpression (MYCTg) synergizes with KRASG12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRASG12D alone. Genome-wide ribosomal footprinting of MYCTg;KRASG12 tumors compared with KRASG12D revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRASG12D tumors by functional, non-canonical upstream open reading frames in its 5′ untranslated region, which is bypassed in MYCTg;KRASG12D tumors to evade immune attack. We show that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYCTg;KRASG12D tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies.

2019-01-07 | GSE105147 | GEO

Translation control of the immune checkpoint in cancer and its therapeutic targeting.

Project description:Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly achieved remains largely unresolved. Here, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show that MYC overexpression (MYCTg) synergizes with KRASG12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRASG12D alone. Genome-wide ribosomal footprinting of MYCTg;KRASG12 tumors compared with KRASG12D revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRASG12D tumors by functional, non-canonical upstream open reading frames in its 5' untranslated region, which is bypassed in MYCTg;KRASG12D tumors to evade immune attack. We show that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYCTg;KRASG12D tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies.

| S-EPMC6613562 | biostudies-literature

Therapeutic Targeting of the p300/CBP Bromodomain Enhances the Efficacy of Immune Checkpoint Blockade Therapy

Project description:Therapeutic Targeting of the p300/CBP Bromodomain Enhances the Efficacy of Immune Checkpoint Blockade Therapy

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Targeting Glycomes Sensitizes Ovarian Tumors to Immune Checkpoint Blockade

Project description:Targeting Glycomes Sensitizes Ovarian Tumors to Immune Checkpoint Blockade

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Antibody-lectin chimeras for glyco-immune checkpoint blockade

Project description:Despite the curative potential of checkpoint blockade immunotherapy, most patients remain unresponsive to existing treatments. Glyco-immune checkpoints – interactions of cell-surface glycans with lectin, or glycan-binding, immunoreceptors – have emerged as prominent mechanisms of immune evasion and therapeutic resistance in cancer. Here, we describe antibody-lectin chimeras (AbLecs), a modular platform for glyco-immune checkpoint blockade. AbLecs are bispecific antibody-like molecules comprising a cell-targeting antibody domain and a lectin “decoy receptor” domain that directly binds glycans and blocks their ability to engage inhibitory lectin receptors. AbLecs potentiate anticancer immune responses including phagocytosis and cytotoxicity, outperforming most existing therapies and combinations tested. By targeting a distinct axis of immunological regulation, AbLecs synergize with blockade of established immune checkpoints. AbLecs can be readily designed to target numerous tumor and immune cell subsets as well as glyco-immune checkpoints, and therefore represent a new modality for cancer immunotherapy.

2025-08-13 | PXD063934 | Pride

Targeting Glycomes Sensitizes Ovarian Tumors to Immune Checkpoint Blockade II

Project description:Targeting Glycomes Sensitizes Ovarian Tumors to Immune Checkpoint Blockade II

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Multi-omic Profiling of Central Nervous System Leukemia Identifies mRNA Translation as a Therapeutic Target

Project description:Central nervous system (CNS) dissemination of B-precursor acute lymphoblastic leukemia (B-ALL) has poor prognosis and remains a therapeutic challenge. Here we performed targeted DNA sequencing, transcriptional and proteomic profiling of paired leukemia infiltrating cells in the bone marrow (BM) and CNS of xenografts. Genes governing mRNA translation were upregulated in CNS leukemia, and subclonal genetic profiling confirmed this in both BM-concordant and BM-discordant CNS mutational populations. CNS leukemia cells were exquisitely sensitive to the translation inhibitor omacetaxine mepesuccinate, which reduced xenograft leptomeningeal disease burden. Proteomics demonstrated greater abundance of secreted proteins in CNS infiltrating cells including complement component 3 (C3) and drug targeting of C3 influenced CNS disease in xenografts. CNS infiltrating cells also exhibited selection for stemness traits and metabolic reprogramming. Overall, our study identifies therapeutic targeting of mRNA translation as a novel therapeutic approach for B-ALL leptomeningeal disease.

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N-myc mediated translation control is a therapeutic vulnerability in medulloblastoma

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Restoring PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance

Project description:Immune checkpoint inhibitors (ICIs) are a type of cancer treatment that work by targeting molecules on immune cells that can inhibit the immune system's ability to attack cancer cells. One such checkpoint molecule is PD-1, which is found on the surface of T cells (a type of immune cell) and helps to prevent them from attacking healthy cells. When PD-1 binds to its ligand (a molecule on the surface of some cells), it sends a signal to the T cell to \\"turn off\\" and not attack the cell. This mechanism is important in preventing the immune system from attacking healthy cells, but it can also be exploited by cancer cells to avoid detection and destruction by the immune system. In this study YUMM2.1 mouse tumour cells were implanted subcutaneously. The effect of IFN-γ-pre-treatment, PARP14 inhibition and PD-1 antibody treatment are reported by RNA-seq.

2023-08-22 | E-MTAB-12872 | biostudies-arrayexpress

Immune Checkpoint Regulation of Pulmonary Fibrosis [bulk RNA-seq]

Project description:Fibroblasts from idiopathic pulmonary fibrosis (IPF) patients acquire an invasive phenotype that is essential for progressive fibrosis. The immune checkpoint ligand CD274 (PD-L1) is up-regulated on invasive lung fibroblasts, regulated by P53 and FAK signaling, and drives lung fibrosis in a humanized IPF model in mice. Targeting CD274high fibroblasts blunted invasion in vitro and attenuated fibrosis in vivo, suggesting that CD274 may be a novel therapeutic target in IPF.

2019-05-17 | GSE118933 | GEO

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