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Phase separation of chimeric antigen receptor promotes immunological synapse maturation and persistent cytotoxicity

ABSTRACT: Phase separation of chimeric antigen receptor promotes immunological synapse maturation and persistent cytotoxicity

PROVIDER: PRJNA1167671 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30853000_1.fastq.gz	Fastqsanger.gz
	SRR30853000_2.fastq.gz	Fastqsanger.gz
	SRR30853001_1.fastq.gz	Fastqsanger.gz
	SRR30853001_2.fastq.gz	Fastqsanger.gz
	SRR30853002_1.fastq.gz	Fastqsanger.gz

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Phase separation of chimeric antigen receptor promotes immunological synapse maturation and persistent cytotoxicity

Project description:Major challenges of CAR-T cell therapy include poor antigen sensitivity and cell persistence. Here we report a solution to these issues by exploiting CAR phase separation. We found that incorporation of an engineered CD3e motif, EB6I, to the conventional 28Z or BBZ CAR induced self-phase separation through cation-π interactions. EB6I CAR can form a mature immunological synapse with CD2 corolla to transduce efficient antigen and costimulatory signaling, while its tonic signaling remains at low levels. Functionally, EB6I CAR-T cells exhibited improved signaling and cytoxicity against low-antigen tumor and persistent tumor killing function. In multiple primary and relapsed murine tumor models, EB6I CAR-T cells exerted better antitumor functions than conventional CAR-T cells against blood and solid cancers. This study thus unveils a new CAR engineering strategy to improve CAR-T cell immunity by leveraging molecular condensation and signaling integration.

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Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite

Project description:Tumors employ various strategies to evade immune surveillance. Central nervous system (CNS) has multiple features to restrain immune response，because cranial inflammation can rapidly develop into lethal brain edema. However, whether tumors and CNS share similar programs of immune tolerance is elusive. Here, we analyzed transcriptomic and metabolomic profiles of tumors from patients with HER2+ breast cancer, who received trastuzumab, anti-PD-L1 antibodies and docetaxel (KN035-TH-HER2 study). We found that a neuronal metabolite N-acetylaspartate (NAA) and its synthetase N-acetyltransferase 8-like (NAT8L) are enriched in resistant tumors. In CNS, NAA is released during brain inflammation. We showed that NAT8L attenuates brain inflammation in experimental autoimmune encephalomyelitis (EAE) and impairs anti-tumor immunity by inhibiting cytotoxicity of NK cells and CD8+ T cells via NAA. Mechanistically, NAA disrupts the formation of immunological synapse by inducing K542 acetylation of lamin A, which inhibits the integration between lamin A and SUN2 and consequently impairs polarization of lytic granules in NK cells and CD8+ T cells. Our study uncovered that tumor cells mimic the anti-inflammatory protective barrier of CNS to evade from anti-tumor immunity and NAT8L is a potential target to enhance efficacy of anti-cancer agents

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Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite

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Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite

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