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Epigenetic analysis of tumor-specific CD8 T cells in murine and solid tumors

ABSTRACT: Epigenetic analysis of tumor-specific CD8 T cells in murine and solid tumors

PROVIDER: PRJNA351717 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR4568540_1.fastq.gz	Fastqsanger.gz
	SRR4568540_2.fastq.gz	Fastqsanger.gz
	SRR4568550_1.fastq.gz	Fastqsanger.gz
	SRR4568550_2.fastq.gz	Fastqsanger.gz
	SRR4568560_1.fastq.gz	Fastqsanger.gz

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Epigenetic analysis of tumor-specific CD8 T cells in murine and solid tumors

Project description:ATACseq analysis of dysfunctional CD8 T cells in progressing tumors. The overall goal of this study was to elucidate chromatin states associated with functional unresponsiveness in tumor-specific CD8 T cells in the context of mouse and human tumors. As comparison we also investigated chromatin state dynamics associated with CD8 T cells differentiation to functional effector and memory T cells during an acute listeria infection.

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Project description:Phosphoinositide 3-kinase δ (PI3Kδ) plays key roles in lymphocytes and inhibitors targeting this PI3K have been approved for hematological malignancies. While preclinical data in hematological and solid tumor models have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumor immunity, the impact of PI3Kδi in human solid tumors remains unknown. Here, we assessed the effects of the PI3Kδi AMG319 in patients with early stage head and neck cancer in a neoadjuvant, double-blind and placebo-controlled randomised phase-II trial. We find that PI3Kδ inhibition decreases tumor-infiltrating TREG cells and causes heightened cytotoxic potential of tumor-infiltrating CD8+ and CD4+ T cells. Loss of intratumoral TREG cells and an increase in the frequency of activated TREG cells in the blood post-treatment are indicative of systemic effects on TREG cell tissue retention and maintenance. At the chosen AMG319 dosing, the occurrence of immune-related adverse events caused treatment discontinuation in 43% of drug-treated patients, further suggestive of systemic effects on TREG cells. Consistent with this notion, in a murine syngeneic tumor model, PI3Kδi caused a decrease in TREG cells in both tumor and non-malignant tissues and affected TREG subtype composition, maintenance and functionality.

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Immunomodulatory effects of PI3Kδ inhibition in murine and human solid tumors [human]

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Immunomodulatory effects of PI3Kδ inhibition in murine and human solid tumors [human]

Project description:Immunomodulatory effects of PI3Kδ inhibition in murine and human solid tumors [human]

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Immunomodulatory effects of PI3Kδ inhibition in murine and human solid tumors [mouse]

Project description:Immunomodulatory effects of PI3Kδ inhibition in murine and human solid tumors [mouse]

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IL-7-primed bystander CD8 tumor-infiltrating lymphocytes optimize the antitumor efficacy of T-cell engager immunotherapy in solid tumors

Project description:Bispecific T-cell engagers (TCEs) show promising clinical efficacy in blood tumors, but their application to solid tumors with immunosuppressive environments remains challenging. Here, we show that Fc-fused IL-7 (rhIL-7-hyFc) changes the intratumoral CD8 T cell landscape, allowing TCE-immunotherapy to function effectively in solid tumors. In order to explore the transcriptomic changes induced by rhIL-7-hyFc or a combination of rhIL-7-hyFc and TCE treatment at the clonal level, we performed scRNA/TCR-seq.

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Cooperation between Constitutive and Inducible Chemokines Enables T-cell Engraftment and Immune Attack in Solid Tumors

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