Rejuvenation of tumour-specific T cells through bispecific antibodies targeting PD-L1 on dendritic cells.
Longchao LiuJiahui ChenJoonbeom BaeHuiyu LiZhichen SunCasey TimmermanEric J HsuChuanhui HanJian QiaoYang-Xin FuPublished in: Nature biomedical engineering (2021)
Bispecific T-cell engagers (BiTEs) preferentially targeting tumour-associated antigens and stimulating CD3-mediated signalling are being used in patients to treat acute B-cell lymphoblastic leukemia. However, the potency of BiTEs in solid tumours is limited by their short half-life and their severe toxicity at relevant therapeutic doses. Here we report the design and in vivo performance of a bispecific antibody that simultaneously targets the murine T-cell co-receptor CD3ε and the murine immune checkpoint programmed-death ligand 1 (PD-L1). In multiple syngeneic tumour models, the bispecific antibody generated higher antitumour immune responses than conventional BiTEs targeting tumour-associated antigens and CD3ε. We found that the durable antigen-specific T-cell responses resulted from the rejuvenation of CD8 T cells, owing to the blockade of PD-L1 on dendritic cells (but not on tumour cells) and co-stimulation by B7-1&2 (a peripheral membrane protein on dendritic cells). Bispecific T-cell engagers targeting dendritic cells rather than tumour cells may represent a general means of T-cell rejuvenation for durable cancer immunotherapy.
Keyphrases
- dendritic cells
- immune response
- regulatory t cells
- induced apoptosis
- cancer therapy
- cell cycle arrest
- end stage renal disease
- oxidative stress
- newly diagnosed
- acute myeloid leukemia
- chronic kidney disease
- nk cells
- platelet rich plasma
- drug delivery
- drug induced
- prognostic factors
- cell proliferation
- inflammatory response
- peritoneal dialysis
- intensive care unit
- pi k akt
- oxide nanoparticles