Dual inhibition of TGF-β and PD-L1: a novel approach to cancer treatment

Transforming growth factor-beta (TGF-beta) 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-beta signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial-to-mesenchymal transition, and angiogenesis. Meanwhile, PD-L1 expression inactivates cytotoxic T cells and restricts immunosurveillance in the TME. Anti-PD-L1 therapies have been approved for the treatment of various cancers, but TGF-beta signaling in the TME is associated with resistance to these therapies. In this review, we discuss the importance of the TGF-beta and PD-L1 pathways in cancer, as well as clinical strategies using combination therapies that block these pathways separately or approaches with dual-targeting agents (bispecific and bifunctional immunotherapies) that may block them simultaneously. Currently, the furthest developed dual-targeting agent is bintrafusp alfa. This drug is a first-in-class bifunctional fusion protein that consists of the extracellular domain of the TGF-beta RII receptor (a TGF-beta 'trap') fused to a human immunoglobulin G1 (IgG1) monoclonal antibody blocking PD-L1. Given the immunosuppressive effects of the TGF-beta and PD-L1 pathways within the TME, colocalized and simultaneous inhibition of these pathways may potentially improve clinical activity and reduce toxicity.

Automated summary

Transforming growth factor-beta (TGF-beta) and programmed death-ligand 1 (PD-L1) have immunosuppressive functions in the tumor microenvironment (TME) and inhibiting these pathways can improve clinical outcomes and reduce toxicity.