Ontology highlight
ABSTRACT:
PROVIDER: PRJNA735916 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14758337_1.fastq.gz | Fastqsanger.gz | |||
| SRR14758337_2.fastq.gz | Fastqsanger.gz | |||
| SRR14758338_1.fastq.gz | Fastqsanger.gz | |||
| SRR14758338_2.fastq.gz | Fastqsanger.gz | |||
| SRR14758339_1.fastq.gz | Fastqsanger.gz |
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Project description:Chimeric Antigen Receptor (CAR) T-cell therapy can be effective in treating human cancer but, loss/downregulation of the antigen recognized by the CAR poses a major obstacle to tumor eradication. Here, we report an approach for vaccine boosting CAR T-cells, which triggers engagement of the endogenous immune system to stop antigen-negative tumor escape. Vaccine boosting enhanced CAR T-cell polyfunctionality, increased tumor antigen uptake by dendritic cells, and elicited priming of endogenous anti-tumor T cells (antigen spreading). This process required vaccine-induced enhancements in CAR T IFN-γ production and a metabolic shift in CAR T-cells toward oxidative phosphorylation. Antigen spreading induced by vaccine-boosted CAR-T therapy enabled control of solid tumors with substantial pre-existing heterogeneity, which was further enhanced by genetically amplifying CAR T IFN-γ expression. Thus, CAR T cell-derived IFN-γ plays a critical role in promoting endogenous anti-tumor immunity, and vaccine boosting provides a clinically-translatable strategy to drive such responses against solid tumors.
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Project description:T cell infiltration is essential for immune checkpoint inhibitors to be effective in treating solid cancers. Through a bioinformatic pipeline, we identified a target gene SUN1 that might relate to modulating immune cell infiltration and immune response. Thus, we generated one Sun1_knockout CT26 cell line (Sun1_KO) and two control CT26 cell lines (Sun1_Control) using CRISPR-Cas9. By performing RNA-seq on cultured cells, tumors grown in syngeneic model, and purified tumor cells from tumors grown in syngeneic model, we set out to understand how mouse Sun1 can affect immune-related pathways and immune cell infiltration and anti-PD1 efficacy in BALB/c mice.
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