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

Bispecific T-cell engagers (BiTEs) that preferentially target tumor-associated antigens to engage CD3 signaling have been approved to treat acute B-cell lymphoblastic leukemia. However, their applications in solid tumors have been hampered by short half-life and severe toxicity at therapeutic doses. Whether antigen-specific T cells would be rejuvenated by directing to tumor cells remains unclear. To address this, we designed a bispecific antibody (BsAb) which simultaneously targets CD3 and immune checkpoint PD-L1. Compared with conventional tumor cell targeting BsAb, PD-L1xCD3 generates superior anti-tumor immune responses in vivo. By single-cell sequencing of tumor-infiltrated T cells in different BiTE treatment, we found that PD-L1xCD3 treatment generate unique T cell subsets in the tumor microenvironment which contribute to the increased antitumor efficacy and reduced side effect. Tumor infiltrated T cells in different bispecific antibody treatment

优先靶向肿瘤相关抗原以介导CD3信号通路激活的双特异性T细胞衔接蛋白（Bispecific T-cell engagers, BiTEs）已获批用于治疗急性B淋巴细胞白血病。然而，这类蛋白在实体瘤中的应用却因治疗剂量下半衰期较短、毒性较强而受到限制。通过将抗原特异性T细胞定向募集至肿瘤细胞能否使其功能复苏，目前仍不明确。为解决这一科学问题，我们设计了一种同时靶向CD3与免疫检查点PD-L1的双特异性抗体（Bispecific antibody, BsAb）。与传统的靶向肿瘤细胞的双特异性抗体相比，PD-L1xCD3可在体内诱导更优异的抗肿瘤免疫应答。我们对不同双特异性T细胞衔接蛋白处理组中的肿瘤浸润T细胞开展单细胞测序分析后发现，PD-L1xCD3处理可在肿瘤微环境中形成独特的T细胞亚群，该亚群有助于提升抗肿瘤疗效并降低不良反应。不同双特异性抗体处理后的肿瘤浸润T细胞