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Selective CAR-T cell mediated B cell depletion suppresses interferon signature in SLE [Bcells]

ABSTRACT: Selective CAR-T cell mediated B cell depletion suppresses interferon signature in SLE [Bcells]

PROVIDER: PRJNA1100403 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28679748_1.fastq.gz	Fastqsanger.gz
	SRR28679748_2.fastq.gz	Fastqsanger.gz
	SRR28679749_1.fastq.gz	Fastqsanger.gz
	SRR28679749_2.fastq.gz	Fastqsanger.gz
	SRR28679750_1.fastq.gz	Fastqsanger.gz

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Project description:CAR T cell therapy has revolutionized the treatment of hematologic malignancies, but its efficacy in solid tumors remains limited due to the immunosuppressive nature of the tumor microenvironment and the inability of T cells to persist and traffic to the tumor site. While current strategies focus on enhancing CAR T cell activity through costimulatory molecules and cytokines, a critical yet often overlooked factor is the competition for nutrients between tumor cells and T cells in the nutrient-deprived tumor microenvironment. To address this challenge, we employed a selective metabolic refueling (MR) strategy by providing T cells with inosine as an alternative fuel source for growth and functionality. In this study, we engineered CAR T cells to co-express a membrane-bound CD26 and a cytoplasmic adenosine deaminase 1 (ADA1) fused to an anti-CD3 scFv. ADA1 irreversibly converts both intracellular and extracellular adenosine to inosine, overcoming adenosine-mediated immunosuppression and providing T cells with inosine for growth. The inclusion of an anti-CD3 scFv fusion partner and overexpressing CD26 boosts ADA1 capture in a membrane proximal manner, providing inosine for T cells and minimizing feeding the tumor cells. We demonstrate that ADA1 is conditionally secreted in an autocrine manner in response to CD3/CD26 stimulation and that it activates CAR T cells through trans-signaling in a tumor-specific manner. In addition, we show that, compared to unmodified CAR T cells, CD26-overexpressing CAR T cells have better migration capacity and are less susceptible to TGF-β1 suppression. Finally, we demonstrate that, in mice models of human hepatocellular carcinoma (GPC3-MR-CAR) and human non-small cell lung cancer (HER2-MR-CAR), metabolically refueled CAR T cells (MR-CAR) are more efficient in reducing tumor growth than unmodified CAR T cells. Thus, selective refueling CAR T cells using ADA1 and CD26 holds promise for improving the efficacy of CAR T cell therapy of solid tumors.

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Selective CAR-T cell mediated B cell depletion suppresses interferon signature in SLE [Bcells]

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