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Deconstructing synthetic inflammasomes in tumors drives diverse antitumor responses

ABSTRACT: Deconstructing synthetic inflammasomes in tumors drives diverse antitumor responses

PROVIDER: PRJNA1086391 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28288474_1.fastq.gz	Fastqsanger.gz
	SRR28288474_2.fastq.gz	Fastqsanger.gz
	SRR28288475_1.fastq.gz	Fastqsanger.gz
	SRR28288475_2.fastq.gz	Fastqsanger.gz
	SRR28288476_1.fastq.gz	Fastqsanger.gz

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Deconstructing synthetic inflammasomes in tumors drives diverse antitumor responses

Project description:Inflammasomes are cardinal defense machines that utilize cytokine and immunogenic cell death components to engage the immune system against pathogens. On the other hand, inflammasomes have ambiguous and context-dependent roles in cancers that are known to downregulate effectors of immunogenic cell death. In this study, we deconstructed inflammasomes by introducing one or both inflammasome signaling arms in diverse types of tumors regardless of the expression of endogenous inflammasome components. To induce immunogenic cell death, we designed tightly regulated GSDMD variants comprising different pore-forming capabilities and diverse modes of activation. We show that electroporation of plasmids encoding the pyroptotic component into B16 melanoma tumors leads to tumor regression and complete remission in a quarter of treated animals. The inflammatory cytokines IL-1β and IL-18, along with the T-cell activator IL-12, did not provide protection when produced solely within tumors. However, they significantly boosted anti-tumor immunity when combined with pyroptosis. Careful selection of immunostimulatory molecules is imperative as a combination of IL-1β and IL-18 or the introduction of IFNγ antagonizes the protective action of pyroptosis by upregulation of several immune checkpoints. Additionally, we show that deconstruction of inflammasomes locally, without inducing systemic inflammation, provides protection against distant tumors and proves effective across various tumor types. Deconstructed inflammasomes are thus a powerful, tunable and tumor-agnostic strategy to enhance antitumor responses to even the most resilient types of tumors.

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Hedgehog Induced ZFYVE21 Activates T Cell Intrinsic, NLRP3 Inflammasomes to Promote Chronic Inflammation

Project description:ZFYVE21 is a novel Rab5 effector involved in immune signaling whose functions in vivo are undefined. Using humanized mouse models and patient specimens, we describe a T cell-autonomous role for ZFYVE21 in promoting chronic inflammation. Following ischemia reperfusion injury (IRI), endothelial cells (ECs) produce Hedgehog (Hh) ligands. Hh ligands induce expression of ZFYVE21 in a “Ptchhi” cell population (CD3+CD4+CD45RO+Ptch1hiPD-1hi) that is highly responsive to Hh signaling and which display vigorous EC-mediated recruitment and effector responses in vivo. Mechanistically, following IFN-gamma-dependent priming, Hh-induced ZFYVE21 modulates T cell intrinsic, NLRP3 inflammasome activity in an Akt-dependent manner to allow IL-18-mediated potentiation of IFN-gamma responses. Hh-induced NLRP3 inflammasomes and T cell-specific ZFYVE21 augment vascular sequelae of chronic inflammation. Moreover, Ptchhi T cells highly expressing ZFYVE21 are expanded in IRI patients, and frequencies of these cells are modulated by Hh signaling. Hh-induced ZFYVE21 activates T cell intrinsic, NLRP3 inflammasomes to promote chronic inflammation.

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Low-potassium triggers epithelial NLRP3/ASC-driven kidney inflammation independently of inflammasomes

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