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. 2022 Apr 26;13:779691. doi: 10.3389/fimmu.2022.779691

Table 2.

Biomarkers for predicting immune-related adverse events.

Circulating blood counts

  • ALC (>2.6 k/μL) (41)

  • AEC1 (>240/μL; >125/μL) (90, 91)

  • AMC (>0.29k/uL) (41)

  • Platelet count (>145 k/μL) (41)

  • NLR1 (<3; <2.3) (41, 92)

  • dNLR (>3) (37)

  • PLR1 (< 534; < 180) (26, 41).

  • ANC (<6.5) (41)

  • MLR (< 0.73) (41)

  • Lower T regulatoryGI cells at the baseline (2.5% in irAE group versus 8.4% in non-irAE group) (93).

  • CD8+ cells (clonal expansion > 55) (94)

  • Early T cell receptor repertoire diversity (95)

  • Drop-in WBC count (by 59%) and relative lymphocytic count (by 32%) from baseline 2 (96)
Cytokines

  • Lower baseline levels2 of TNF-α, IL-6, IL8, IP-10, CXCL9, CXCL10, CXCL11, and CXCL19. Post-treatment significant rise in the levels of IL-6, CXCL5, CXCL9, and CXCL10 levels (23, 33, 93, 97–101)

  • Higher IL-72 at the baseline and exponential rise (102)

  • Significant rise in Granulocyte colony-stimulating factor (G-CSF) at 4 weeks compared to baseline (23)

  • Serial Interferon-gamma (IFN-γ), decrease to <10 IU/ml 3-6 weeks after starting ICI (103)

  • A significant rise (mean rise from 8.4mg.L to 52.7mg/L) C-reactive protein (CRP) (104)
Autoantibodies

  • Higher soluble CTLA-4 (>200 pg/ml) (105)

  • Autoantibody detection - anti-GNAL, anti-ITM2B, and anti-CD74, rheumatoid factor, anti-nuclear and anti-thyroid antibody, anti-thyroid peroxidase antibody, anti-thyroglobulin antibody (106–110)

  • Lower baseline (≤ 45μg/L) soluble major histocompatibility complex class I chain-related protein A (MICA), lower soluble CD25 (median level was 630 pg/ml in irAE group), and a significant rise in soluble CD163 (± 21.3%) (93, 101, 111)

  • Anti-BP180 IgG (median was 6.1 U/mL) (112)
Serum proteins

  • Higher baseline albumin (≥3.6 g/dl) (23, 44)

  • Significant drop in post-treatment leptin levels from baseline (23)

  • Higher baseline thyroid-stimulating hormone levels (1.67 mIU/L) (108–110)

  • Elevated troponin for cardiac irAE (50)

  • lactate dehydrogenase (LDH) ≥245 U/L (88)
HLA genotypes

  • HLA types - HLA-DRB1*11:01skin and HLA-DQB1*03:01GI alleles (113)

  • Predominance of HLA-DR4 (114)

  • HLA-DR15, B52 and Cw12 irAE-pitutary (115).

  • HLA-DRB1*04: 05 for irAE-arthritis (116)

  • HLA-DPA1*02:02 and DPB1*05:01 in irAE-diabetes (117)
MicroRNA and gene expression profiling

  • Increased irAE risk: mapped to One variant A allele in GABRP SNP rs11743438; One variant A allele in GABRP SNP rs11743435; one variant allele A in the DSC2 SNP JHU_20.57183980; one variant allele G in the BAZ2B SNP rs56328422; one variant allele T in the SEMA5A SNP rs3026321

  • Post-treatment (3-week) increased expression of CD177GI (12.2 fold higher in ir-AE group than non-irAE group) and CEACAM1GI genes (118)

  • Suppressed miR-146a gene (by SNP s2910164) (119)

  • Reduced irAE risk: mapped to RGMA, ANKRD42, PACRG, GLIS3, ROBO1 genes (120).
Intestinal microbiotaGI

  • Abundant Bacteroidetes phylum, specifically Bacteroidaceae, Rikenellaceae, and Barnesiellaceae (Deficient polyamine transport and vitamin B biosynthesis) (121)

  • Abundant Faecalibacterium genus and other Firmicutes at baseline (93)

  • At the phylum level, low Bacteroidetes/Firmicutes ratio; at the genus level, a relative abundance of Alistipes, low Bacteroides, and high Blautia, Lachnospiraceae, and Faecalibacterium (122)
Stool testingGI

  • Stool calprotectin (> 150mcg/g) and positive lactoferrin in colitis-irAE (123–127).
Cardiac workup

  • ECG abnormalities, and low echocardiographic global longitudinal strain (GLS) may predict cardiac-irAE (50)

1two values represent results of two different studies; 2Cut-off values are not well established; GI Specific for Gastrointesinal adverse events; skin Specific for dermal adverse events; ICI, immune check-point inhibitor; irAE, immune-related adverse events; (ALC); (AMC), absolute monocyte count; (AEC), absolute eosinophilic count; platelet count; (ABC), absolute basophil count; (NLR), neutrophil-lymphocyte ratio; (PLR), platelet lymphocyte ratio; (MLR), monocyte to lymphocyte ratio; (eGFR), Estimated glomerular filtration rate; (HER2), human epidermal growth factor receptor 2; (VEGF), Vascular endothelial growth factor; (TKI), Tyrosine Kinase Inhibitor; (HLA), Human leukocyte antigen; (AML), acute myeloid leukemia; and (MDS), myelodysplastic syndromes; SNP, single nucleotide polymorphisms.