Combination Therapy of Bispecific Protein of Anti-PD-L1 Fused with TGF- β Receptor in Cancer

Abstract

Transforming growth factor β (TGF-β) and programmed death-ligand 1 (PD-L1) initiate signaling pathways with complementary, nonredundant immunosuppressive functions in the tumor microenvironment (TME). In the TME, dysregulated TGF-β signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial-mesenchymal transition, and angiogenesis. Meanwhile, PD-L1 expression inactivates cytotoxic T cell function and restricts immunosurveillance in the TME. Anti-PD-L1 therapies have been approved for the treatment of various cancers, while TGF-β signaling in the TME is associated with resistance to anti-PD-L1 therapies. Here, we have reviewed the rationale of the TGF-β and PD-L1 pathways in cancer and discussed current strategies using combination therapies that block these pathways separately or approaches with dualtargeting agents that may block the pathways simultaneously. Importantly, according to current clinical results, we propose the developing strategy of combination treatment with two or more agents.