Cited by 180TGF-β signaling in diseasesCancer Immunotherapy and BiomarkersCancer Cells and Metastasis

A novel bifunctional anti-PD-L1/TGF-β Trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells

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David, Justin M., Dominguez, Charli, McCampbell, Kristen K., Gulley, James L., Schlom, Jeffrey, Palena, Claudia·2017·OncoImmunology

Abstract

Mesenchymalization is a cellular and molecular program in which epithelial cells progressively lose their well-differentiated phenotype and adopt mesenchymal characteristics. Tumor mesenchymalization occurs during the progression of cancer to metastatic disease, and is also associated with resistance to multiple therapeutics, including killing by cytotoxic immune cells. Furthermore, tumor cells can evade immune destruction by upregulating the checkpoint molecule PD-L1, and emerging research has found higher PD-L1 expression in mesenchymalized tumors. Here, the association between TGF-β1-mediated mesenchymalization and PD-L1 was investigated in non-small cell lung cancer cells (NSCLC). TGF-β1 was found to upregulate PD-L1 gene transcription in a Smad2-dependent manner, and a positive association between PD-L1 and phosphorylated Smad2 was found in NSCLC tumors. The potential to target these 2 negative immune regulators with a single agent was investigated using M7824, a novel clinical-stage bifunctional agent that targets both PD-L1 and TGF-β. Treatment of NSCLC cells with M7824 in vitro and in vivo attenuated features of TGF-β1-mediated mesenchymalization, including mesenchymal marker expression, proliferation suppression, and chemoresistance. These findings demonstrate that upregulation of tumor cell PD-L1 is a novel mechanism of TGF-β1-induced immunosuppression in NSCLC, and that treatment with M7824 has the potential to simultaneously block both tumor mesenchymalization and PD-L1-dependent immunosuppression.

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  • The balance of CD4+ Th1, Th2, Th17, and Treg cells can shift dramatically following therapy, with reprogramming from one CD4+ T cell subset to another.

    “The balance of CD4+ Th1, Th2, Th17 and Treg cells can shift dramatically following therapy, with reprogramming from one CD4+ T cell subset towards another368,369 (Figure 4).”

    From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [368]

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Authors
David, J. M., Dominguez, C., McCampbell, K. K., Gulley, J. L., Schlom, J., & Palena, C.
Affiliations
National Institutes of Health (US)
Corresponding author
Palena, Claudia
Venue
OncoImmunology
Published
2017-07-13
Volume
6
Issue
10
Pages
e1349589
ISSN
  • 2162-4011 (ISSN-L)
  • 2162-402X
OpenAlex
W2734696348
Cited by
180
References
61
Citations by year
2026: 8 · 2025: 17 · 2024: 17 · 2023: 21 · 2022: 27 · 2021: 36 · 2020: 31 · 2019: 10 · 2018: 10 · 2017: 3
FWCI
6.03
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • OncoImmunology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
PD-L1, TGF-β1, non-small cell lung cancer, Smad2 signaling, immunosuppression, chemoresistance, immune checkpoint blockade, tumor microenvironment

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