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Table 1 Nonspecific biomarker of irAEs

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

Biomarker Author Year Cancer type Patient number Treatment Correlation between biomarker and irAEs Possible hypothesis
CRP Abolhassani AR [18] 2019 MM 37 Anti-PD-1 Anti-CTLA-4 CRP elevation can predict the onset of irAEs in patients treated with ICIs in the absence of infectious disease. Tumor-promoting inflammation could cause a systemic inflammatory response;CRP level was positively associated with the infiltration of CD8 + T cell and Treg cell which could activate the systemic inflammatory response.
IL-6 Okiyama N [19] 2017 MM 22 Anti-PD-1 The IL-6 level was significantly increased in the patients with psoriasiform dermatitis after nivolumab treatment. Overactivation of the immune system;Excessive release of inflammatory cytokines.
Valpione S [15] 2018 MM 140 Anti-CTLA 4 A lower baseline level of IL-6 was strongly associated with the development of irAEs.
Blood cell count Fujisawa Y [20] 2017 MM 101 Anti-PD-1 The increase of WBC counts and the decrease of relative lymphocyte counts were closely related to the incidence of grade 3–4 irAEs. Conventional blood cell counts could be a crude reflection of the body’s immune state, but the mechanism is unclear.
Diehl A [21] 2017 Multiple solid tumors (lung cancer, MM, RCC, urothelial, HNSCC, Merkel cell carcinoma, colon cancer) 167 Anti-PD-1 Higher baseline and increase of absolute lymphocyte and eosinophil counts after ICIs treatment were strongly associated with the development of irAEs.
Nakamura Y [22] 2019 MM 45 Anti-PD-1 The elevation of absolute eosinophil count at baseline and relative eosinophil count at 1 month might be valuable biomarkers to predicte endocrine irAEs.
Cytokines Khan S [23] 2019 Multiple solid tumors (lung cancer, kidney cancer, MM, head/neck cancer, liver cancer, bladder cancer) 65 Anti-PD-1/L1 Anti-CTLA 4 The up-regulation of various cytokines after ICIs treatment was closely related to the occurrence of irAEs, especially the induced CXCL9, 10, 11 and 13. Activate T cell;Excessive release of cytokines;Various cytokines have powerful pro-inflammatory activities, including stimulating immune cell recruitment, proliferation, survival, differentiation, and effector functions, and many of these cytokines (such as IL-1A, IL-1B, IL-2, IFN 2, and IL-12P70) are associated with inflammation, which is the basis of autoimmune diseases.
Lim SY [24] 2019 MM 98 Anti-PD-1 Anti-CTLA 4 Eleven cytokines, including G-CSF, GMCSF, Fractalkine, FGF-2, IFN-2, IL-12p70, IL-1a, IL-3 1B, IL-1RA, IL-2, IL-13, were significantly upregulated in patients with severe irAEs at baseline and early during treatment.
TMB Bomze D [25] 2019 Multiple solid tumors 16,397 Anti-PD-1 There is a significant positive correlation between high TMB and irAEs during anti-PD-1 therapy in a variety of solid tumors While fighting against neoantigens, T cells could also cross-react with the corresponding wild-type antigens in normal tissues, resulting in damage to normal tissues.
sCLTA-4 Pistillo MP [26] 2018 MM 113 Anti-CTLA-4 Higher baseline levels of sCTLA-4 were closely associated with irAEs, especially the gastrointestinal adverse events. Elevated levels of sCTLA-4 might block the interactions between full-length CTLA-4 expressed by autoreactive T cells and Tregs as well as B7 ligands, thus enhance the cytotoxicity of T cells and reduce the immunosuppression function of Treg cell.
  1. irAEs immune related adverse events, ICIs immune checkpoint inhibitors, CRP C reactive protein, MM malignant melanoma, Anti-PD-1/L1 anti-programmed cell death protein 1/ligand 1, Anti-CTLA-4 anti-cytotoxic T lymphocyte associated antigen-4, IL-6 interleukin 6, RCC renal cell carcinoma, HNSCC head and neck squamous cell carcinoma, WBC white blood cell, NLR neutrophil-lymphocyte ratio, TMB tumor mutation burden, sCLTA-4 soluble CTLA-4, flCTLA-4 full-length CTLA-4