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

Table 1 Blood cell biomarkers of immune-related adverse events

Biomarker	ICI type	Patients	Study cohort	irAE type	Judgment	Ref.
CD4+ T cell	CTLA-4, PD-1	17	8/17 (47%) irAEs, among them, 4 multiple irAEs	NA	CD4+ T cells increased during irAEs	[34]
CD8+ T cell	CTLA-4, PD-1	17	8/17 (47%) irAEs, among them, 4 multiple irAEs	NA	CD8+ T cells increased during irAEs	[34]
B cell	CTLA-4, PD-1	23	13/23 (57%) irAEs	NA	Low levels of CD21lo B cells at baseline in the irAE group, and significantly increase after the first cycle of combined CTLA-4 and PD-1 inhibitor treatment	[35]
White blood cell count and relative lymphocyte count	PD-1	101	38/101 (38%) irAEs. Among them, 6 multiple irAEs, 2 combined irAEs, 4 continuous irAEs	NA	An increase in white blood cell and a decrease in relative lymphocyte count were associated with the occurrence of G3/4 irAEs	[36]
Absolute eosinophil count	PD-1	321	18% ICI pneumonia in patients with an average age of 62.7 years	Lung irAEs	The absolute eosinophil count of patients with ICI-pneumonia was significantly higher than that of no ICI-pneumonia patients	[37]
Absolute lymphocyte count	PD-1	171	73/171 (42.7%) irAEs	NA	At 2 wk after initiation of treatment, an increase in absolute lymphocyte count was significantly associated with an increased risk of irAEs	[38]
Neutrophil/lymphocyte ratio	PD-1	275	121/275 (44.0%) irAEs, 86 with one irAEs, 26 with two irAEs, 9 with three or more irAEs, Severe irAEs (> grade 3) occurred in 29 (10.5%)	Lung irAEs	Increased neutrophil/lymphocyte ratio can predict the severity of subsequent irAEs pneumonia with high accuracy, and the higher the NLR value, the more severe irAEs occurs	[39]
	PD-1	92	45/92 (48.9%) irAEs	NA	Before treatment, neutrophil/lymphocyte ratio > 2.3 was significantly associated with an increased risk of irAEs	[40]
Lymphocyte/monocyte ratio	PD-1	92	45/92 (48.9%) irAEs	NA	Before treatment, lymphocyte/monocyte ratio > 1.6 significantly reduced the risk of irAEs	[40]
Absolute monocyte count	CTLA-4, PD-1, PD-L1	470	33% irAEs	NA	The incidence of irAEs was significantly associated with higher baseline absolute monocyte count	[41]
Platelet count	CTLA-4, PD-1, PD-L1	470	33% irAEs	NA	The incidence of irAEs was significantly associated with higher baseline platelet count	[41]
Platelet/lymphocyte ratio	CTLA-4, PD-1, PD-L1	470	33% irAEs	NA	The incidence of IrAEs was significantly associated with lower baseline platelet/lymphocyte ratio	[42]

irAEs: Immune-related adverse events; ICI: 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.

Table 3 Autoantibodies and metabolic abnormalities biomarkers of immune-related adverse events

Biomarker	ICI type	No. of patients	Study cohort	irAEs type	Judgment	Ref.
Thyroglobulin	CTLA-4, PD-1	26	13/26 (50%) irAEs	Thyroid dysfunction	The titers of TgAb and TPO in the irAE group were significantly higher after ICI treatment	[43]
TgAb, TPOAb	CTLA-4, PD-1	26	13/26 (50%) irAEs	Thyroid dysfunction	Serum Tg level in irAE group increased significantly before/after treatment	[43]
Thyroid-stimulating hormone	CTLA-4, PD-1	96	36/96 (37.5%) irAEs	Thyroid gland irAEs	High thyroid-stimulating hormone levels at baseline are associated with a higher risk of hypothyroidism	[65]
Anti-pituitary antibodies	CTLA-4, PD-1	62	17/62 (27%) ICI- ICI-induced isolated adrenocorticotropic hormone deficiency, 5/62 (8%) ICI-induced hypophysitis	Pituitary gland irAEs	Patients with ICI-induced isolated adrenocorticotropic hormone deficiency showed positive anti-pituitary antibodies at baseline and after treatment, and patients with ICI-induced hypophysitis showed positive anti-pituitary antibodies after treatment and before onset, and anti-pituitary antibodies can be used as biological predictors	[66]
Anti-GNAL and anti-ITM2B autoantibody		9 + 20	Study cohort: 3 hypophysitis, 6 non-hypophysitis; Confirmed cohort: 5 pituitaritis, 15 non-pituitaritis	Pituitary gland irAEs	Anti-GNAL and anti-ITM2B were associated with irAE hypophysitis	[67]
Anti-CD74 autoantibody		8 + 32	Study cohort: 2 pneumonia, 6 non-pneumonia; Confirmed cohort: 10 pneumonia, 22 non-pneumonia	Lung irAEs	Anti-CD74 autoantibody is associated with irAE pneumonia	[67]
Antinuclear antibody	PD-1	83	6/18 (33.3%) irAEs in antinuclear antibody positive group. 21/65 (32.3%) irAEs in antinuclear antibody negative group		The incidence of irAEs increased with antinuclear antibody titer	[68]
Urine retinol binding protein/urine creatinine	CTLA-4, PD-1, PD-L1	50	37/50 (74%) irAEs	Kidney irAEs	During the occurrence of ICI-induced acute kidney injury, the urine retinol binding protein/urine creatinine value of patients was significantly higher	[69]
Guanylate binding protein 5, Guanylate binding protein 6	CTLA-4, PD-1	19	All 19 patients were suspected of cardiac irAEs	Heart irAEs	Guanylate binding proteins 5 and 6 were significantly upregulated in ICI-induced myocarditis compared with dilated cardiomyopathy and virus-induced myocarditis	[70]

irAEs: Immune-related adverse events; ICI: Immune checkpoint inhibitors; TgAb: Anti-thyroglobulin antibodies; TPOAb: Thyroid peroxidase antibodies.

Table 4 Immunogenetic biomarkers of immune-related adverse events

Biomarker	ICI type	No. of patients	Study cohort	irAEs type	Judgment	Ref.
HLA-DR15, HLA-B52, HLA-Cw12	CTLA-4, PD-1	11	9 HLA-DR15, 7 HLA-B52, 7 HLA-CW12	Pituitary irAEs	In 11 patients, gene frequencies of HLA-DR15, HLA-B52, and HLA-CW12 were significantly higher in the irAEs-developing group	[73]
HLA- Cw12, HLA- DR15, HLA- DQ7 and HLA- DPw9	CTLA-4, PD-1	62	17/62 (27%) ICI-induced isolated adrenocorticotropic hormone deficiency, 5/62 (8%) ICI-induced hypophysitis	Pituitary irAEs	The positive rates of HLA-CW12, HLA-DR15, HLA-DQ7, and HLA-DPW9 were significantly higher in patients with ICI-induced isolated adrenocorticotropic hormone deficiency, and the positive rates of HLA-CW12 and HLA-DR15 were significantly higher in patients with ICI-induced hypophysitis	[66]
HLA-DR4	PD-1, PD-L1	2960	27/2960 (0.9%) insulin dependent diabetes mellitus	Insulin-dependent diabetes mellitus	The expression of HLA-DR4 gene is related to the incidence of insulin dependent diabetes mellitus	[74]
HLA-B*27:05	PD-L1	290	7/290 (2%) ICI-associated encephalitis	Encephalitis	The occurrence of irAEs encephalitis was significantly correlated with HLA-B *27:05 expression	[75]
HLA-DRB1*11:01, HLA-DQB1*03:01	PD-1, PD-L1, CTLA-4	102	59/102 (58%) irAEs	Itching, colitis	The expression of HLA-DRB1*11:01 was related to the occurrence of pruritus. The expression of HLA-DQB1*03:01 was associated with colitis	[77]
Pre-existing autoimmune disease	CTLA-4, PD-1, PD-L1	4438	It was divided into strict criteria group for autoimmune diseases, lenient criteria group and control group		The prevalence of irAEs was higher in the strict criteria group and the loose criteria group than in the group without pre-existing autoimmune disease	[78]
Single nucleotide polymorphism (30 markers)	CTLA-4, PD-1, PD-L1	89	44/89 (49%) irAEs		A total of 30 variants or single nucleotide polymorphism were identified. Twelve of these were associated with an increased risk of irAEs and 18 with a reduced risk	[87]
MIR146A SNP rs2910164	PD-1, PD-L1	167	The study was conducted in mice and validated with data from cancer patients treated with ICI		MIR146A single nucleotide polymorphism rs2910164 can be used as a biomarker to predict severe irAEs in ICI patients	[90]

irAEs: Immune-related adverse events; ICI: Immune checkpoint inhibitors; HLA: Human leukocyte antigen.