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 welldocumented. 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.

Pro- and Anti-Inflammatory Responses in Severe COVID-19-Induced Acute Respiratory Distress Syndrome—An Observational Pilot Study

“…GDF-15 is a member of the anti-inflammatory TGF- β superfamily. While it has been shown to reduce clearance of human rhinovirus and to enhance the risk for virus-induced lung inflammation in mice ( 11 ), it counteracts inflammation ( 8 ), increases the ability of tissues to tolerate inflammatory damage via metabolic adaptation ( 9 ), and reduces tissue infiltration of immune cells ( 8 ). We thus hypothesize that induction of GDF-15 is an adaptation to restore a disturbed balance between pro- and anti-inflammatory cytokines.…”

“…Another feature besides viral infectivity and inflammation is the host response and tissue tolerance. An emerging modulator of immune responses ( 8 ) and mediator of inflammation tissue tolerance is the multi-functional anti-inflammatory cytokine growth and differentiation factor 15 (GDF-15) ( 9 ), which physiologically promotes immunotolerance during pregnancy. In mouse models GDF-15 protects the kidney, liver, and other organs from adverse consequences of bacterial and viral sepsis ( 9 , 10 ).…”

Evaluating the Relationship of GDF-15 with Clinical Characteristics, Cardinal Features, and Survival in Multiple Myeloma

“…GDF-15 also plays a part in the inflammatory response, and the work by the group of Luan et al showed a GFRAL-related central metabolic adaptation via the regulation of sympathetic outflow and triglyceride metabolism [ 34 ]. Importantly, it has also been emphasized that the manifold actions ascribed to GDF-15 in prior research are limited by contamination of recombinant GDF-15 with TGF β [ 33 , 35 , 36 ]. This indicates that the previous implication of GDF-15 effects on Smad2/3 activity or TGF β RII requires caution and reappraisal [ 36 ].…”

“…Importantly, it has also been emphasized that the manifold actions ascribed to GDF-15 in prior research are limited by contamination of recombinant GDF-15 with TGF β [ 33 , 35 , 36 ]. This indicates that the previous implication of GDF-15 effects on Smad2/3 activity or TGF β RII requires caution and reappraisal [ 36 ]. On the other hand, it should also be noted that GDF-15 exerts direct effects on immune cells and its immunomodulatory capacity may be independent of centrally regulated mechanisms [ 36 ].…”

“…This indicates that the previous implication of GDF-15 effects on Smad2/3 activity or TGF β RII requires caution and reappraisal [ 36 ]. On the other hand, it should also be noted that GDF-15 exerts direct effects on immune cells and its immunomodulatory capacity may be independent of centrally regulated mechanisms [ 36 ]. Further understanding of whether and if the central (GFRAL) and peripheral (local, fast-acting) GDF-15-associated mechanisms exist and interact with myeloma biology is warranted.…”