Table 1.

Putative predictors of immune adverse events associated with immune checkpoint inhibitors.

Genotype	HLA-DR4 association with ICI-associated diabetes in patients with a variety of cancers treated with anti-PD-1/PD-L1 (42). HLA-DR4 association with ICI-associated diabetes in patients treated with anti-PD-1/PD-L1 (43). HLA-DRB1*04:05 association with ICI-induced arthritis in patients with a variety of cancers (69). HLA-DRB1*11:01 association with ICI-induced pruritis and HLA-DQB1* 03:01 and colitis in patients with non-small lung cancer (NSCLC) or melanoma treated with anti-PD-1, anti-CTLA-4 or their combination (71).
Pre-existing autoimmune disease	irAEs are more frequent and occur sooner in patients with autoimmune disease treated with anti-PD-1 (106, 107). Pre-existing autoimmune disease associated with modest increases in hospitalization with irAEs in patients treated with ICIs (108).
Baseline autoantibodies	Thyroid autoantibodies (anti-TPO, anti-tg) at baseline increases the risk of thyroid dysfunction in patients treated with nivolumab or pembrolizumab (85–87, 109). Baseline autoantibody signatures, such as those targeting TNF-α signaling pathways may be predictive of irAEs in patients with melanoma treated with anti-CTLA-4, anti-PD-1 or their combination (110). Skin irAEs may be more frequent in patients with positive RF at baseline in patients with NSCLC treated with nivolumab or pembrolizumab (87).
Baseline cytokine levels	Baseline IL-17 serum levels may predict ICI-induced colitis in patients with melanoma treated with ipilimumab (65). Baseline IL-6 serum levels were associated with higher risk of toxicity in melanoma patients treated with ipilimumab (111). Cytokine toxicity score predictive of severe irAEs in patients with melanoma treated with ipilimumab, anti-PD-1 or their combination (112). Baseline serum levels of IL-1β, IL-2, and GM-CSF predict thyroid dysfunction in patients with a variety of cancers (66).
Immune cell changes	Reduction in circulating B cells, increase in CD2lo PD-1+ B cells and plasmablasts precede adverse events in patients with melanoma treated with ipilimumab, anti-PD-1 or their combination (113). Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio may predict appearance of irAEs in patients with NSCLC treated with anti-PD-1/PD-L1 (114). High baseline absolute eosinophil count (AEC) (> 135/μl) correlates with the risk of irAEs in patients with melanoma, renal cell carcinoma, and NSCLC treated with anti-CTLA-4 (115, 116). High proliferative index in circulating effector and control memory CD8+ T lymphocytes at early time points in melanoma patients treated with CICB who developed ≥ grade 3 irAEs (96). Lower expression of surface CD28 and CD27 on circulating CD4+ and CD8+ effector T lymphocytes of melanoma patients treated with CICB who did not develop severe irAEs (96). Increased activated CD4 memory T cells and TCR diversity in peripheral blood are associated with severe irAEs in patients with melanoma treated with anti-PD-1 or anti-PD-1 and ipilimumab combination (79).
Microbiome	Bacteroidetes phylum may be protective for development of colitis in melanoma patients treated with ipilimumab (75). Faecalibacterium may be predictive of colitis in melanoma patients treated with ipilimumab (74). Bacteroides intestinalis is associated with ≥ grade 3 colitis in patients with melanoma treated with combined ipilimumab and PD-1 blockade (96).
Tumor burden	High tumor burden is associated with higher risk of severe irAEs in patients with NSCLC (117).