BCL2 inhibition reveals a dendritic cell-specific immune checkpoint that controls tumor immunosurveillance

ABSTRACT: We developed a screening platform in which immortal dendritic cell (DC) precursors can be genetically manipulated and then de-immortalized and differentiated into DCs for functional in vitro assays, as well for adoptive transfer into syngeneic tumor-bearing mice to explore their capacity to instate immunosurveillance. A genome-wide CRISPR screen led to the identification of BCL2 as an endogenous inhibitor of DC function. Knockout of BCL2 in DCs enhanced antigen presentation and the expression of activation markers in vitro, as well as the capacity of DCs to control tumor growth in vivo and to synergize with PD-1 blockade. These effects where phenocopied by the pharmacological BCL2 inhibitors venetoclax and navitoclax, both of which required DCs of the cDC1 subtype to efficiently reduce the growth of orthotopic lung cancers and fibrosarcomas. Thus, solid tumors failed to respond to venetoclax and navitoclax in mice constitutively devoid of cDC1 cells due to the knockout of Batf3, and this defect was reversed by the infusion of DCs. Moreover, depletion of cDC1 cells by systemic injection of cytochrome c reduced the therapeutic efficacy of BCL2 inhibitors alone or in combination with PD-1 blockade. In vivo treatment with venetoclax caused cDC1 cells to express several activation markers, both in mice and in patients. In conclusion, genetic and pharmacological BCL2 inhibition unveils a DC-specific immune checkpoint that restrains tumor immunosurveillance

ORGANISM(S): Mus musculus

PROVIDER: GSE218062 | GEO | 2023/11/15

REPOSITORIES: GEO