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Gulley JL, Schlom J, Barcellos-Hoff MH, et al. Dual inhibition of TGF-β and PD-L1: a novel approach to cancer treatment. Mol Oncol. 2021;doi: 10.1002/1878-0261.13146.
Gulley, J. L., Schlom, J., Barcellos-Hoff, M. H., Wang, X. J., Seoane, J., Audhuy, F., Lan, Y., Dussault, I., & Moustakas, A. (2021). Dual inhibition of TGF-β and PD-L1: a novel approach to cancer treatment. Molecular oncology, . https://doi.org/10.1002/1878-0261.13146
Gulley, James L, et al. "Dual inhibition of TGF-β and PD-L1: a novel approach to cancer treatment." Molecular oncology vol. (2021). doi: https://doi.org/10.1002/1878-0261.13146
Gulley JL, Schlom J, Barcellos-Hoff MH, Wang XJ, Seoane J, Audhuy F, Lan Y, Dussault I, Moustakas A. Dual inhibition of TGF-β and PD-L1: a novel approach to cancer treatment. Mol Oncol. 2021 Dec 01; doi: 10.1002/1878-0261.13146. Epub 2021 Dec 01. PMID: 34854206.
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Mol Oncol. 2021 Dec 01; doi: 10.1002/1878-0261.13146. Epub 2021 Dec 01.

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

Molecular oncology

James L Gulley, Jeffrey Schlom, Mary Helen Barcellos-Hoff, Xiao-Jing Wang, Joan Seoane, Francois Audhuy, Yan Lan, Isabelle Dussault, Aristidis Moustakas

Affiliations

  1. Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  2. Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  3. Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
  4. Department of Pathology, University of Colorado, Aurora, CO, USA.
  5. ICREA, Vall D'Hebron Institute of Oncology, CIBERONC, Universitat Autonoma de Barcelona, Barcelona, Spain.
  6. EMD Serono, Billerica, MA, USA.
  7. Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

PMID: 34854206 DOI: 10.1002/1878-0261.13146

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.

© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

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

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