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

• Published in: Molecular oncology Vol. 16; no. 11; pp. 2117 - 2134
• Main Authors: Gulley, James L., Schlom, Jeffrey, Barcellos‐Hoff, Mary Helen, Wang, Xiao‐Jing, Seoane, Joan, Audhuy, Francois, Lan, Yan, Dussault, Isabelle, Moustakas, Aristidis
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.06.2022; John Wiley and Sons Inc; Wiley
• Subjects: Angiogenesis; Antibodies; Antibodies, Monoclonal - pharmacology; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; Cancer therapies; Cytokines; Cytotoxicity; Dendritic cells; Fibroblasts; Fibrosis; Fusion protein; Genotype & phenotype; Granulocytes; Humans; immune checkpoint inhibitor; Immunoglobulin G; Immunosurveillance; Immunotherapy; Kinases; Ligands; Lymphocytes; Lymphocytes T; Medical prognosis; Mesenchyme; Metastasis; Monoclonal antibodies; Neoplasms - drug therapy; Neutrophils; PD-L1; PD-L1 protein; Peptides; Review; Signal transduction; TGF-beta; TGF‐β; Transforming Growth Factor beta - antagonists & inhibitors; Transforming growth factor-b; Tumor Microenvironment; Tumors; Vascular endothelial growth factor; PD-L1; TGF-β; immune checkpoint inhibitor; tumor microenvironment
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.13146

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. The TGF‐β and PD‐L1 signaling pathways have complementary, nonredundant functions in the tumor microenvironment. Dysregulated TGF‐β signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial–mesenchymal transition, and angiogenesis, while PD‐L1 restricts immunosurveillance. We review existing strategies for simultaneous inhibition of these pathways, highlighting dual‐targeting agents that may provide colocalized, simultaneous inhibition.