Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint

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.

Keywords: anorexia; autoimmunity; cancer; growth/differentiation factor-15 (GDF-15); immune exclusion; immunotherapy; macrophage inhibitory cytokine-1 (MIC-1); pregnancy.

Figure 1

GDF-15 in different physiological and pathological contexts. GDF-15 stimulates or inhibits different cellular processes via GFRAL and potentially other still unknown receptors in various physiological and pathophysiological situations. DC, Dendritic cells; T_reg, regulatory T cells.

Figure 2

The role of GDF-15 in immune modulation. In various pathological conditions, GDF-15 correlates inversely with the ability of T cell to infiltrate the tumor, placenta, or the infarcted myocardium. As the most prominent physiological expression of GDF-15 is found in the placenta it may have evolved to protect the (semi-allogeneic) fetus by establishing a protective barrier at the placenta-fetal junction, thus shielding the fetus against maternal T cells.