Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint
Open accessAbstract
Growth/differentiation factor-15 (GDF-15), also named macrophage inhibitory cytokine-1, is a divergent member of the transforming growth factor β superfamily. While physiological expression is barely detectable in most somatic tissues in humans, GDF-15 is abundant in placenta. Elsewhere, GDF-15 is often induced under stress conditions, seemingly to maintain cell and tissue homeostasis; however, a moderate increase in GDF-15 blood levels is observed with age. Highly elevated GDF-15 levels are mostly linked to pathological conditions including inflammation, myocardial ischemia, and notably cancer. GDF-15 has thus been widely explored as a biomarker for disease prognosis. Mechanistically, induction of anorexia via the brainstem-restricted GDF-15 receptor GFRAL (glial cell-derived neurotrophic factor [GDNF] family receptor α-like) is well-documented. GDF-15 and GFRAL have thus become attractive targets for metabolic intervention. Still, several GDF-15 mediated effects (including its physiological role in pregnancy) are difficult to explain via the described pathway. Hence, there is a clear need to better understand non-metabolic effects of GDF-15. With particular emphasis on its immunomodulatory potential this review discusses the roles of GDF-15 in pregnancy and in pathological conditions including myocardial infarction, autoimmune disease, and specifically cancer. Importantly, the strong predictive value of GDF-15 as biomarker may plausibly be linked to its immune-regulatory function. The described associations and mechanistic data support the hypothesis that GDF-15 acts as immune checkpoint and is thus an emerging target for cancer immunotherapy.
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Elevated levels of GDF15 have been linked to tumor growth and poor prognosis in cancer patients.
“Elevated levels of GDF15 have been linked to tumor growth and poor prognosis in cancer patients raising the question as to whether GDF15 serves as a tumor suppressor or promoter and a target for the treatment of cancer (84, 85, 99).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [85]
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- Authors
- Wischhusen, J., Melero, I., & Fridman, W. H.
- Affiliations
- University of Würzburg (DE)
- Clinica Universidad de Navarra (ES)
- Inserm (FR)
- Corresponding author
- Wischhusen, Jörg
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2020-05-19
- Volume
- 11
- Pages
- 951-951
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC7248355
- OpenAlex
- W3026163675
- Cited by
- 506
- References
- 203
- Citations by year
- 2026: 79 · 2025: 94 · 2024: 112 · 2023: 79 · 2022: 84 · 2021: 49 · 2020: 9
- FWCI
- 8.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Deposito Adademico Digital Universidad De Navarra (University of Navarra) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Rheumatology › GDF15 and Related Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- GDF15, MIC-1, GFRAL, immune checkpoint, cancer immunotherapy, biomarkers, immunomodulation, pregnancy, myocardial infarction, autoimmune disease, inflammation, anorexia, TGF-beta superfamily
- MeSH terms
- Immune Checkpoint Inhibitors, Animals, Autoimmune Diseases, Female, Homeostasis, Humans, Myocardial Infarction, Neoplasms, Placenta, Pregnancy, Biomarkers, Mice, Growth Differentiation Factor 15, Immunomodulation
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