Table 1.

Nonspecific biomarker of irAEs

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.

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