Abstract
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.
Highlights
Growth/differentiation factor 15 (GDF-15) is known as macrophage inhibitory cytokine (MIC)-1, non-steroidal anti-inflammatory drug-inducible gene (NAG)-1, placental transforming growth factor-beta, prostate-derived factor (PDF), and placental bone morphogenetic protein (PLAB)
This review aims to summarize the physiological and pathophysiological functions of GDF-15 (Figure 1), with a main focus on its role in cancer and cancer immunotherapy
By demonstrating that GDF-15 limits the recruitment of infiltrating pro-inflammatory cells by interfering with chemokine signaling and β2-integrin/lymphocyte functionassociated antigen 1 (LFA-1) activation, this study offered the first mechanistic explanation for anti-inflammatory effects of GDF-15
Summary
Growth/differentiation factor 15 (GDF-15) is known as macrophage inhibitory cytokine (MIC)-1, non-steroidal anti-inflammatory drug-inducible gene (NAG)-1, placental transforming growth factor-beta (pTGFB), prostate-derived factor (PDF), and placental bone morphogenetic protein (PLAB). It remains to be determined whether the effects of induced GDF-15 expression in pathological conditions such as metabolic diseases, tissue injury, inflammation, and cancer, all depend on GFRAL. A GDF-15-dependent effect on tissue infiltration by pro-inflammatory immune cells in sepsis was not observed; rather, a different mechanism via activation of GFRAL inducing β-adrenergic signaling to stimulate the release of triglycerides from the liver was proposed. Apart from its effects on appetite and body weight regulation, it protects the fetus by inhibiting T cells, protects other tissues against excessive inflammation, and is induced in many pathologies where GDF-15 function appears to be context-dependent. In patients with stage I and II non-small cell lung cancer, multivariate Cox regression survival analysis showed that high GDF-15 in serum was an independent risk factor for reduced overall survival (HR = 3.37, 95% CI: 1.09–10.42, p = 0.035) [81]. This immune effect is reflected in the tremendous predictive power of Immunoscore [137, 138] which defines the immune “fitness” of a given tumor host interaction-based on the localization of CD8 T lymphocytes in the invasive front and the Frontiers in Immunology | www.frontiersin.org
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