Biomarkers associated with immune-related adverse events induced by immune checkpoint inhibitors

Table 2 Cytokines biomarkers of immune-related adverse events

Biomarker	ICI type	The number of patients	Study cohort	irAEs type	Judgment	Ref.
IL-1β, IL-2, GM-CSF	CTLA-4, PD-1	26	13/26 (50%) irAEs	Thyroid dysfunction	ICI-thyroid dysfunction patients had higher levels of serum IL-1β, IL-2 and GM-CSF at baseline	[43]
IL-8, G-CSF, MCP-1	CTLA-4, PD-1	26	13/26 (50%) irAEs	Thyroid dysfunction	The early decrease of IL-8, G-CSF and MCP-1 levels was significantly correlated with the occurrence of thyroid irAEs	[43]
G-CSF, Leptin and RANTES	PD-1	38	11/38 (29%) irAEs	NA	Serum G-CSF and RANTES levels were significantly increased and leptin levels were significantly decreased in irAE patients. RANTES was statistically correlated with irAE incidence	[48]
Il-6, CRP	CTLA-4, PD-1	16	13/16 (81%) irAEs	NA	In the early stages of irAEs, serum IL-6 and CRP levels were significantly higher than at baseline	[52]
CRP	CTLA-4, PD-1	37	100% irAEs, 25/37 (68%) two or more irAEs, 14/37 (38%) multiorgan irAEs	NA	CRP was significantly increased from baseline to the onset of irAEs	[53]
IL-6	CTLA-4, PD-1	17	12/17 (71%) irAEs	NA	The peak of IL-6 predicted the occurrence of irAEs	[54]
sMICA	CTLA-4	77	47% irAEs	NA	A high baseline serum level of sMICA predicted a low incidence of irAEs	[57]
sCD163	PD-1	1	The 58-year-old patient had metastatic melanoma	HLH	High levels of sCD163 were elevated during irAEs	[59]
IL-17, Ang-1, CD40L	CTLA-4, PD-1	52	28/52 (54%) grade 1 to 2 irAEs, 24/52 (46%) grade 3 to 4 irAEs	irAE-related dermatitis and pneumonia	Baseline plasma concentrations of Ang-1 and CD40L were significantly higher in patients with irAEs dermatitis; baseline IL-17 in patients with irAEs pneumonia was significantly different from that in non-irAE patients	[60]
IL-6, CXCL2, CCL20, CXCL8, CCL23	CTLA-4, PD-1, PD-L1	78	34% irAEs with receiving anti-PD1 /PDL1, 60% irAEs with receiving combination therapy. 1 irAEs with receiving anti-CTLA4 monotherapy	NA	At baseline, IL-6, CXCL2, CCL20, CXCL8 and CCL23 levels were significantly higher in the irAEs group	[63]
CXCL9, CXCL10, CXCL11 and CXCL19	CTLA-4, PD-1, PD-L1	78	34% irAEs with receiving anti-PD1 /PDL1, 60% irAEs with receiving combination therapy. 1 irAEs with receiving anti-CTLA4 monotherapy	NA	At baseline, patients with irAEs had lower levels of CXCL9, CXCL10, CXCL11, and CXCL19	[63]
CYTOX score (G-CSF, GMCSF, Fractalkine, FGF-2, IFNα2, IL-12p70, IL-1a, IL- 1B, IL-1RA, IL-2, IL-13)	CTLA-4, PD-1	98 + 49	98 patients were in the discovery cohort and 49 patients were in the validation cohort	NA	High expression of 11 cytokines in the CYTOX score was associated with severe irAEs	[64]

sMICA: Soluble major histocompatibility complex class I chain-related protein A; CRP: C-reactive protein; irAEs: Immune-related adverse events; ICI: Immune checkpoint inhibitors; IL: Interleukin; GM-CSF: Granulocyte-macrophage colony-stimulating factor; sCD: Soluble CD; HLH: Hemophagocytic lymphohistiocytosis; RANTES: Regulated on activation, normal T cell expressed and secreted; MCP-1: Monocyte chemotactic protein-1; CXCL: C-X-C motif chemokine ligand; C motif chemokine ligand; FGF-2: Fibroblast growth factor 2; IFNα 2: Interferon alpha 2.