Targeting dendritic cells with a PD-L1 based bispecific antibody rejuvenates specific anti-tumor T cells

Abstract Bispecific T-cell engagers (BiTEs) that preferentially target tumor-associated antigens (TAA) to reengage CD3 signaling have been approved to treat acute B-cell lymphoblastic leukemia. However, their applications in solid tumors have been hampered due to short half-life, weak anti-tumor activity, and severe toxicity at therapeutic doses. To explore new targets, we designed a bispecific antibody (BsAb) which simultaneously targets CD3 and immune checkpoint PD-L1. Compared with conventional TAA based targeting, PDL1xCD3 generates far superior anti-tumor immune responses in vivo. Mechanistically, blockade of PD-L1 on dendritic cells instead of tumor cells can potently rejuvenate preexisting tumor reactive CD8 T cells in a B7-1/2 dependent manner for a durable anti-tumor responses. This study argues that targeting DC-T cell instead of current tumor-T cell can achieve much better T cell rejuvenation in BsAb therapy.