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Vaccine-primed CAR T-cells reject antigen-heterogenous tumors via host immunity

ABSTRACT: Vaccine-primed CAR T-cells reject antigen-heterogenous tumors via host immunity

PROVIDER: PRJNA875449 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21380760_1.fastq.gz	Fastqsanger.gz
	SRR21380760_2.fastq.gz	Fastqsanger.gz
	SRR21380761_1.fastq.gz	Fastqsanger.gz
	SRR21380761_2.fastq.gz	Fastqsanger.gz
	SRR21380762_1.fastq.gz	Fastqsanger.gz

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Vaccine-primed CAR T-cells reject antigen-heterogenous tumors via host immunity

Project description:Chimeric Antigen Receptor (CAR) T-cell therapy effectively treats human cancer, but loss of the antigen recognized by the CAR poses a major obstacle. We found that in vivo vaccine boosting of CAR T-cells triggers engagement of the endogenous immune system to circumvent antigen-negative tumor escape. Vaccine-boosted CAR-T promoted dendritic cell (DC) recruitment to tumors, increased tumor antigen uptake by DCs, and elicited priming of endogenous anti-tumor T-cells (antigen spreading). This process was accompanied by shifts in CAR-T metabolism toward oxidative phosphorylation and was critically dependent on CAR T-derived IFN-γ. Antigen spreading induced by vaccine-boosted CAR T enabled a proportion of complete responses even when the initial tumor was 50% CAR-antigen-negative, and heterogenous tumor control was further enhanced by genetically amplifying CAR T IFN-γ expression. Thus, CAR T-cell-derived IFN-γ plays a critical role in promoting antigen spreading, and vaccine boosting provides a clinically-translatable strategy to drive such responses against solid tumors.

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