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Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade

ABSTRACT: Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade

PROVIDER: PRJNA327201 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR3727890_1.fastq.gz	Fastqsanger.gz
	SRR3727890_2.fastq.gz	Fastqsanger.gz
	SRR3727900_1.fastq.gz	Fastqsanger.gz
	SRR3727900_2.fastq.gz	Fastqsanger.gz
	SRR3727910_1.fastq.gz	Fastqsanger.gz

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Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade [ATAC-Seq]

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Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade [RNA-Seq]

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Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade.

Project description:Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.

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Aurora A Kinase Inhibition Induces Accumulation of Tumor Cells in Mitosis with Restored Interferon Signaling to Potentiate Response to PD-L1 Immune Checkpoint Blockade [RNA-seq]

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Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade

Project description:This SuperSeries is composed of the SubSeries listed below.

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Aurora A Kinase Inhibition Induces Accumulation of Tumor Cells in Mitosis with Restored Interferon Signaling to Potentiate Response to PD-L1 Immune Checkpoint Blockade [single cell RNA-seq]

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Molecular patterns of resistance to immune checkpoint blockade in melanoma [NanoString GeoMx]

Project description:Tumor cell-containing Regions of Interest from 17 patients with melanoma after progression to Immune Checkpoint Blockade were profiled at the transcriptomic level.

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Tumour mtDNA mutations drive aerobic glycolysis to enhance checkpoint blockade

Project description:Mitochondrial DNA (mtDNA) encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutations in the cancer genome, with truncating mutations in complex I genes being over-represented1 . While mtDNA mutations have been associated with both improved and worsened prognoses in several cancer lineages1–3, whether these mutations are drivers, or exert any functional effect on tumour biology remains controversial. Here we discover that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment of mouse and human cancer in a mutation load-dependent fashion, encouraging an anti-tumour immune response. This subsequently sensitises both mouse and human cancers with high mtDNA mutant heteroplasmy to immune checkpoint blockade. Strikingly, patient lesions bearing >50% mtDNA mutation load demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.

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Project description:Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade

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PRMT1 inhibition activates the interferon pathway to potentiate antitumor immunity and enhance checkpoint blockade efficacy in melanoma

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