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Characterization and comparative analysis of multifunctional natural killer cell engagers (NKCEs) during antitumor responses

ABSTRACT: Characterization and comparative analysis of multifunctional natural killer cell engagers (NKCEs) during antitumor responses

PROVIDER: PRJNA1101020 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28710200_1.fastq.gz	Fastqsanger.gz
	SRR28710200_2.fastq.gz	Fastqsanger.gz
	SRR28710201_1.fastq.gz	Fastqsanger.gz
	SRR28710201_2.fastq.gz	Fastqsanger.gz
	SRR28710202_1.fastq.gz	Fastqsanger.gz

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Characterization and comparative analysis of multifunctional natural killer cell engagers (NKCEs) during antitumor responses

Project description:T cell engagers (TCEs) are transformational oncology therapies but limited in use due to the induction of cytokine release syndrome (CRS). In comparison to T cells, natural killer (NK) cells produce less cytokines upon activation, leading to the exploration of NK cell engagers (NKCEs). However, why NK cells secrete less cytokines such as tumor necrosis factor (TNF) and how NKCEs perform directly against TCEs remain unclear. Here we report that relative to T cells, NK cells have reduced trafficking and processing of TNF. Systematic development and benchmarking studies show that NKCEs can be optimized to engage multiple activating receptors and incorporate the interleukin (IL)-2, thereby increasing their potency and durability. Furthermore, comparative studies of NKCE, IL-2, and TCE therapy in animal tumor models reveal both common and different therapeutic benefits. Our results provide a blueprint for development of multifunctional NKCEs that may serve as an alternative to current TCE therapies.

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Nuclear ACAT1 orchestrates natural killer cell dependent antitumor immunity in colorectal cancer

Project description:Natural killer (NK) cells play pivotal roles in antitumor immunity, yet their connection to tumor metabolism remains unclear. Our systematic analysis of multiomics data and survival data from colorectal cancer (CRC) patients uncovered a novel association between mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) and NK cell infiltration that influences disease progression. ACAT1, a metabolic enzyme involved in reversible conversion of acetoacetyl-CoA to two molecules of acetyl-CoA, exhibits nuclear protein acetylation activity through its translocation. Under immune stimulation, mitochondrial ACAT1 can be phosphorylated at serine 60 (S60) and enters the nucleus; however, this process is hindered in nutrient-poor tumor microenvironments. Nuclear ACAT1 directly acetylates lysine 146 of p50 (NFKB1), attenuating its DNA binding and transcriptional repression activity and thereby increasing the expression of immune-related factors, which in turn promotes NK cell recruitment and activation to suppress colorectal cancer growth. Furthermore, significant associations were found among low nuclear ACAT1 levels, decreased S60 phosphorylation, and reduced NK cell infiltration, as well as poor prognosis in CRC. Our findings reveal an unexpected function of ACAT1 as a nuclear acetyltransferase and elucidate its role in NK cell-dependent antitumor immunity through p50 acetylation.

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Nuclear ACAT1 orchestrates natural killer cell dependent antitumor immunity in colorectal cancer

Project description:Nuclear ACAT1 orchestrates natural killer cell dependent antitumor immunity in colorectal cancer

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Project description:Investigation of global gene expression levels between B cells, Natural killer cells and Natural killer B cells Gene expression profiling using sorted B cells, Natural killer cells and Natural killer B cells from WT mouse spleen. Total RNA extracted from WT cells were quantified by the NanoDrop ND-1000 and RNA integrity was assessed by standard denaturing agarose gel electrophoresis. The sample preparation and microarray hybridization were performed based on the NimbleGenâs standard protocols.

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Expression data from lung and spleen natural killer cells of WT and Kras mice

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Project description:CD1d-restricted invariant natural killer T cells (iNKT cells) mediate strong antitumor immunity when stimulated by glycolipid agonists. However, attempts to develop effective iNKT cell agonists for clinical applications have been thwarted by potential problems with dose-limiting toxicity and by activation-induced iNKT cell anergy, which limits the efficacy of repeated administration. To overcome these issues, we developed a unique bispecific T-cell engager (BiTE) based on covalent conjugates of soluble CD1d with photoreactive analogues of the glycolipid α-galactosylceramide. Here we characterize the in vivo activities of iNKT cell-specific BiTEs and assess their efficacy for cancer immunotherapy in mouse models using transplantable colorectal cancer or melanoma tumor lines engineered to express human Her2 as a tumor-associated antigen. Systemic administration of conjugated BiTEs stimulated multiple iNKT cell effector functions including cytokine release, secondary activation of NK cells, and induction of dendritic cell maturation and also initiated epitope spreading for tumor-specific CD8+ cytolytic T-cell responses. The antitumor effects of iNKT-cell activation with conjugated BiTEs were further enhanced by simultaneous checkpoint blockade with antibodies to CTLA-4, providing a potential approach for combination immunotherapy. Multiple injections of covalently stabilized iNKT cell-specific BiTEs activated iNKT cells without causing iNKT cell anergy or exhaustion, thus enabling repeated administration for effective and nontoxic cancer immunotherapy regimens. SIGNIFICANCE: Covalently stabilized conjugates that engage the antigen receptors of iNKT cells and target a tumor antigen activate potent antitumor immunity without induction of anergy or depletion of the responding iNKT cells.

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