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

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-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-β signaling in the TME is associated with resistance to these therapies. In this review, we discuss the importance of the TGF-β 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-βRII receptor (a TGF-β 'trap') fused to a human immunoglobulin G1 (IgG1) monoclonal antibody blocking PD-L1. Given the immunosuppressive effects of the TGF-β and PD-L1 pathways within the TME, colocalized and simultaneous inhibition of these pathways may potentially improve clinical activity and reduce toxicity.

Keywords: PD-L1; TGF-β; immune checkpoint inhibitor; tumor microenvironment.

Fig. 1

TGF‐β‐rich TME promotes survival mechanisms, including angiogenesis, immune suppression, fibrosis, and tumor cell plasticity. Through these mechanisms, TGF‐β signaling prevents antitumor immune responses, limits drug and immune cell access to the tumor, and promotes resistance to therapy. Through these processes, TGF‐β also promotes invasion and metastasis. bFGF, basic fibroblast growth factor; CAF, cancer‐associated fibroblast; CTL, cytotoxic T lymphocyte; DC, dendritic cell; EMT, epithelial–mesenchymal transition; IFN, interferon; MDSC, myeloid‐derived suppressor cell; NK, natural killer; PDGF, platelet‐derived growth factor; TAM, tumor‐associated macrophage; TGF, transforming growth factor; TME, tumor microenvironment; T_reg, regulatory T cell; VEGF, vascular endothelial growth factor.

Fig. 2

TGF‐β and PD‐L1 signaling pathways are implicated in overlapping but nonredundant tumor survival mechanisms, such that simultaneous inhibition may enhance antitumor activity over inhibition of either pathway alone. PD‐1, programmed death 1; PD‐L1, programmed death ligand 1; TGF, transforming growth factor.

Fig. 3

Mechanism of action of bintrafusp alfa, a first‐in‐class bifunctional fusion protein composed of the extracellular domain of TGF‐βRII to function as a TGF‐β ‘trap’ fused to a human IgG1 antibody blocking PD‐L1. Through colocalized, simultaneous inhibition of these pathways, bintrafusp alfa has the potential to enhance immune cell access to the tumor, limit metastasis, and improve response to anticancer therapy. Bintrafusp alfa has the potential to inhibit angiogenesis through suppression of TGF‐β activity via stromal modulation and may restore normal vascular homeostasis, thereby enhancing drug delivery and T‐cell infiltration into the TME. CAF, cancer‐associated fibroblast; EMT, epithelial–mesenchymal transition; NK, natural killer; PD‐1, programmed death 1; PD‐L1, programmed death ligand 1; TAM, tumor‐associated macrophage; TGF, transforming growth factor; TME, tumor microenvironment.