Dual inhibition of TGF-β and PD-L1 : a novel approach to cancer treatment
Gulley, James L. (National Cancer Institute)
Schlom, Jeffrey (National Cancer Institute)
Barcellos-Hoff, Mary Helen (University of California San Francisco)
Wang, Xiao-Jing (University of Colorado)
Seoane Suárez, Joan (Vall d'Hebron Institut d'Oncologia)
Audhuy, Francois (EMD Serono)
Lan, Yan (EMD Serono)
Dussault, Isabelle (Fusion Pharmaceuticals)
Moustakas, Aristidis (Uppsala University)
Universitat Autònoma de Barcelona

Fecha:	2022
Resumen:	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.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Immune checkpoint inhibitor ; PD-L1 ; TGF-β ; Tumor microenvironment
Publicado en:	Molecular oncology, Vol. 16 (january 2022) , p. 2117-2134, ISSN 1878-0261

DOI: 10.1002/1878-0261.13146
PMID: 34854206

18 p, 982.7 KB

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