CAR dendritic cells with CLEC9A or DEC205 domains suppress tumor growth in mice
Dendritic cells carrying chimeric antigen receptors primed T cells and suppressed solid tumor growth in conventional and humanized mice; clinical benefit in patients remains untested.
Chimeric antigen receptor-engineered dendritic cells (CAR-DCs) primed T cells and suppressed tumor growth in mouse models, the authors report in a Nature Immunology paper indexed at doi.org nature.com
doi.orgnature.comOpen source ↗. The work, titled "Rewiring dendritic cell function with CLEC9A and DEC205 CARs", was done by a team that includes Niu, Wang and Pittet. All results are preclinical.
Dendritic cells orchestrate antitumor immunity, but their therapeutic use in solid tumors is limited by cell dysfunction and inadequate activation. The researchers built CAR-DCs to enhance dendritic cell activity and reprogram the tumor microenvironment.
CLEC9A and DEC205 signaling domains
The authors identified the intracellular domains of the endocytic receptors CLEC9A and LY75 (DEC205) as essential for functional CAR-DC activity. CARs that incorporated either domain triggered phosphorylation of spleen tyrosine kinase (SYK) and downstream intracellular signaling.
According to the authors, this signaling enhanced antigen uptake and cross-presentation, which in turn drove T cell expansion and function nature.com
doi.orgnature.comOpen source ↗. Cross-presentation of tumor antigens stimulated CD8-positive T cells to kill tumor cells.
Results in mouse models
In both conventional and humanized mouse models, CAR-DC therapy suppressed tumor growth and promoted expansion of tumor-reactive T cells. The treatment altered cell-to-cell interactions and remodeled the surrounding tumor microenvironment. The authors describe a favorable preclinical safety profile in the animal models tested.
Human HER2-targeted DEC205 and CLEC9A CAR-DCs also mediated effective antitumor responses in experimental models.
The authors conclude that CAR-DCs can serve as a scalable and clinically translatable platform for solid tumor immunotherapy nature.com
doi.orgnature.comOpen source ↗. Clinical benefit in patients has not been shown and is to be examined in future clinical trials. The raw RNA-seq and single-cell RNA-seq datasets from the study are deposited in the Genome Sequence Archive under accession CRA045641.
