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

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

PROVIDER: PRJNA545706 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9153316.fastq.gz	Fastqsanger.gz
	SRR9153317.fastq.gz	Fastqsanger.gz
	SRR9153318.fastq.gz	Fastqsanger.gz
	SRR9153319.fastq.gz	Fastqsanger.gz
	SRR9166100_1.fastq.gz	Fastqsanger.gz

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Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade.

Project description:Interferon-gamma (IFNG) augments immune function yet promotes T cell exhaustion through PDL1. How these opposing effects are integrated to impact immune checkpoint blockade (ICB) is unclear. We show that while inhibiting tumor IFNG signaling decreases interferon-stimulated genes (ISGs) in cancer cells, it increases ISGs in immune cells by enhancing IFNG produced by exhausted T cells (TEX). In tumors with favorable antigenicity, these TEX mediate rejection. In tumors with neoantigen or MHC-I loss, TEX instead utilize IFNG to drive maturation of innate immune cells, including a PD1+TRAIL+ ILC1 population. By disabling an inhibitory circuit impacting PD1 and TRAIL, blocking tumor IFNG signaling promotes innate immune killing. Thus, interferon signaling in cancer cells and immune cells oppose each other to establish a regulatory relationship that limits both adaptive and innate immune killing. In melanoma and lung cancer patients, perturbation of this relationship is associated with ICB response independent of tumor mutational burden.

| S-EPMC6830508 | biostudies-literature

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

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

2019-08-13 | GSE132036 | GEO

Immune checkpoint blockade unleashes aberrant immune responses against the microbiota

Project description:Immune checkpoint blockade unleashes aberrant immune responses against the microbiota

| PRJNA734608 | ENA

Melanoma Sequential Immune Checkpoint Blockade Treatment Sequencing Study

Project description:Melanoma Sequential Immune Checkpoint Blockade Treatment Sequencing Study

| PRJNA397812 | ENA

Immune checkpoint blockade unleashes aberrant immune responses against the microbiota

Project description:Immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 are essential components of the cancer therapeutic armamentarium. The remarkable responses seen with ICIs however, are also accompanied by immune-related adverse events (irAEs). These inflammatory side-effects impact virtually all organ systems, with the most common being the skin and gastrointestinal tract. Here, we establish a mouse model of commensal bacteria-driven skin irAEs and demonstrate that immune checkpoint blockade aberrantly unleashes commensal-specific T cell responses. Such responses caused widespread immune cell infiltration and inflammation throughout the skin, recapitulating the skin irAEs seen in patients treated with ICIs. This skin inflammation was dependent on production of the cytokine IL-17 by commensal-specific T cells, which in turn induced hyperactive responses from macrophages and myeloid cells. Importantly, these responses had long-term consequences, with commensal-specific T cells elicited in the context of ICIs being highly sensitive to re-activation by commensals months later. Together, our results establish a mouse model of skin irAEs and show that immune checkpoint blockade can potentiate aberrant immunity to skin commensals with long-lasting consequences.

2022-06-20 | GSE176030 | GEO

Targeting Glycomes Sensitizes Ovarian Tumors to Immune Checkpoint Blockade

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

| PRJNA1020891 | ENA

IMMUNE CORRELATES OF RESPONSE TO IMMUNE CHECKPOINT BLOCKADE IN ACUTE MYELOID LEUKAEMIA

Project description:IMMUNE CORRELATES OF RESPONSE TO IMMUNE CHECKPOINT BLOCKADE IN ACUTE MYELOID LEUKAEMIA

| PRJNA741507 | ENA

Melanoma Sequential Immune Checkpoint Blockade Treatment Sequencing Study

Project description:<p>Blockade of T cell coinhibitory molecules such as CTLA-4 and PD-1, can activate T cell antitumor response. Although these immune checkpoint blockades (CTLA-4 blockade and PD-1 blockade) have shown durable response, response rate is modest. Therefore, there is a need to find stable biomarkers predictive of response to immune checkpoint blockades and to understand underlying resistance mechanisms. We collected longitudinal tumor biopsies from a cohort of metastatic melanoma patients treated with sequential immune checkpoint blockades and performed whole exome sequencing of this cohort. The comprehensive genomic characterization of tumors enabled identification of higher copy number loss burden as a resistance mechanism and clonal T cell repertoire as a predictive biomarker.</p>

| phs001425 | dbGaP

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.

2024-03-12 | GSE261347 | GEO

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.

2023-11-08 | PXD039705 | Pride

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