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Table 2 Organ-specific biomarker of irAEs

From: The biomarkers related to immune related adverse events caused by immune checkpoint inhibitors

irAEs Biomarker Author Year Cancer type Patient number Treatment Correlation between biomarker and irAEs Possible hypothesis
GI The disorder of gut microbiome Chaput N [27] 2017 MM 26 Anti-CTLA-4 Baseline stool samples without bacteroidetes and with high levels of firmicutes were more likely to develop immune-related colitis. Impaired metabolism of beneficial bacteria;Decreased beneficial bacteria that inhibit inflammation;Microbial-derived products trigger an innate immune response.
CD177 and CEACAM1 Shahabi V [28] 2013 MM 162 Anti-CTLA-4 CD177 and CEACAM1 were highly expressed at baseline and post-baseline in patients with GI irAEs. CD177 and CEACAM1, as activation markers of neutrophils, are involved in immune-mediated intestinal disease.
Peripheral blood mRNA expression (CCL3, CCR3, IL-5, IL-8 and PTGS2) Friedlander P [8] 2018 MM 210 Anti-CTLA-4 Peripheral blood gene expression characteristics (mainly CCL3, CCR3, IL-5, IL-8 and PTGS2) were closely related to the immune-related diarrhea, especially grade 2–4 diarrhea. Up-regulated genes such as CCL3, CCR3, IL-5, IL-8 and PTGS2 are involved in inflammatory immune response.
IL-17 Tarhini AA [29] 2015 MM 35 Anti-CTLA-4 Upregulation of IL-17 level at baseline and 6 weeks after ICIs treatment showed a noteworthy correlation with grade 3 diarrhea/colitis. IL-17, one of the up-regulated central inflammatory cytokines in IBD, was usually inhibited by CTLA-4, but the intervention of ICIs disrupted this ecological balance.
HLA allele Hasan Ali O [30] 2019 NSCLC, MM 102 Anti-PD-1 Anti-CTLA-4 There was a significant correlation between HLA type II variant HLA-dqb1 * 03:01 and immune-related colitis. The presence of common antigens between the tumor and colon tissue causes misleading damage to the gastrointestinal tract by the immune system.
Immune-related pneumonia CD74 Tahir SA [31] 2019 Bladder cancer, prostate cancer 8 Anti-CTLA-4 + Anti-PD-1 The increase of autoantibody CD74 level after ICIs treatment was notably correlated with immune-related pneumonia CD74 stimulates the release of inflammatory mediators;There is a common antigen between the tumor and lung; ICIs disrupts the mechanism that inhibits the inflammatory response of Th2 cells.
Endocrine disorder   Preexisting abnormal antibodies Toi Y [32] 2019 NSCLC 137 Anti-PD-1 Preexisting abnormal antibodies was independently associated with irAEs. Patients with positive RF are more likely to develop dermal irAEs, and thyroid dysfunction is more common in patients with positive antithyroid antibody. T-cells enhance the effect of PD-1 antibody, and might in turn induce B-cells to produce autoantibodies, which will lead to the toxic accumulation effect of pre-existing abnormal autoantibodies, and finally trigger irAEs.
Thyroid dysfunction Abnormal TPOAb Gay S [33] 2019 NSCLC, MPM 28 Anti-CTLA-4 + Anti-PD-1 There was a association between widespread thyroid hypoechogenicity, decreased thyroid volume, elevated TPOAb after ICIs treatment and thyroid dysfunction. ICIs enhance T cell activity against antigens present in healthy tissues and increase pre-existing autoantibody levels.
Hypophysitis GNAL and ITM2B Tahir SA [31] 2019 Prostate cancer, MM, RCC 9 ICI therapy Elevated levels of autoantibodies GNAL and ITM2B are closely related to the immune-related hypophysitis. The qualitative difference in the autoreactive effector T cells between anti-PD-1 / PD-L1 and anti-CTLA-4 treatment; The pituitary endocrine cells themselves might express CTLA-4, making hypophysis a direct target for anti-CTLA-4 antibodies.
Dermatologic toxicity HLA alleles Hasan Ali O [30] 2019 NSCLC, MM 102 Anti-PD-1 Anti-CTLA-4 HLA- drb1 *11:01 was observably related with itching. The presence of common antigens between the tumor and skin causes dermatologic misleading damage.
IL-17 Johnson D [34] 2019 MM 3 Anti-PD-1 Psoriasiform dermatologic toxicity induced by PD-1 inhibitor subsided after treatment with systemic interleukin-IL17A blockade. ICIs enhance the Th17-mediated immune response in susceptible patients.
  1. irAEs immune related adverse events, GI gastrointestinal irAEs, MM malignant melanoma, Anti-CTLA-4 anti-cytotoxic T lymphocyte associated antigen-4, Anti-PD-1/L1 anti-programmed cell death protein 1/ligand 1, IL-8 interleukin 8, IBD inflammatory bowel disease, HLA human leukocyte antigen, IL-17 interleukin 17, NSCLC non-small cell lung cancer, MPM malignant pleural mesothelioma, RCC renal cell carcinoma, ICI immune checkpoint inhibitor