Table 1

Cytokines and chemokines proposed as biomarkers for irAEs

CancerPatients (n)TreatmentKey dataReferences
IL-1 (α, β)Melanoma147Anti-PD-1±anti-CTLA-4Elevated expression of IL-1α and IL-1β at baseline and early during ICI treatment was strongly associated with severe irAEs and integrated into the CYTOX score to predict severe irAE developmentLim et al27
IL-2Melanoma147Anti-PD-1±anti-CTLA-4Increased expression of IL-2 at baseline and early during treatment was strongly associated with severe irAEs and integrated into the CYTOX score for prediction severe irAE occurrenceLim et al27
IL-6Melanoma15NivolumabIncrease in circulating IL-6 after treatment was significantly associated with irAE occurrenceTanaka et al102
Solid tumors285Anti-CTLA-4, anti-PD-1, anti-PD-L1Increased IL-6 during treatment was significantly associated with irAEsPhillips et al41
Solid tumors65Anti-CTLA-4, anti-PD-1, anti-PD-L1IL-6 was significantly elevated at baseline in patients with irAEs versus healthy controlsKhan et al28
Melanoma140IpilimumabBaseline IL-6 was negatively correlated with irAENakamura et al99
Melanoma26IpilimumabLower circulating IL-6 at baseline was significantly associated with ICI-related colitisNakamura et al99
IL-10Solid tumors285Anti-CTLA-4, anti-PD-1, anti-PD-L1Increased IL-10 during treatment was significantly associated with irAEs, including grade 3 or greater irAEsPhillips et al41
IL-12Melanoma147Anti-PD-1±anti-CTLA-4Elevated expression of IL-12p70 at baseline and early during treatment was strongly associated with severe irAEs and integrated into the CYTOX score to predict severe irAE onsetLim et al27
IL-13Melanoma147Anti-PD-1±anti-CTLA-4Increased expression of IL-13 at baseline and early during treatment was strongly associated with severe irAEs and integrated into the CYTOX score for prediction of severe irAE occurrenceLim et al27
IL-17Melanoma35IpilimumabBaseline IL-17 levels were predictive of later development of severe colitis; increased levels of circulating IL-17 may reflect subclinical colitisTarhini et al30
NSCLC13Anti-PD-1/PD-L1IL-17A levels were significantly increased in the serum and BALF at the time of CIP diagnosis compared with baseline, and decreased on clinical recovery or improvementWang et al46
IFN-αMelanoma147Anti-PD-1±anti-CTLA-4IFN-α was significantly upregulated at baseline and early during treatment in severe irAEs and was integrated into the CYTOX score to predict severe irAE developmentLim et al27
G-CSF, GM-CSFMelanoma147Anti-PD-1±anti-CTLA-4Elevated expression of G-CSF and GM-CSF at baseline and early during treatment was strongly associated with severe irAEs and integrated into the CYTOX score for prediction of severe irAE occurrenceLim et al27
CXCL5, soluble CD163Melanoma46NivolumabAbsolute change in CXCL5 and soluble CD163 after initial treatment was elevated in patients with irAEs versus those withoutNakamura et al99
Melanoma26IpilimumabLower circulating soluble CD163 at baseline was significantly associated with ICI-related colitisNakamura et al99
CXCL9, CXCL10, CXCL11, CXCL13Solid tumors65Anti-CTLA-4, anti-PD-1, anti-PD-L1Patterns of CXCL9, CXCL10, CXCL11, CXCL13 had the strongest association with irAEs; lower baseline levels of CXCL9 and CXCL10, and greater increases after treatment was started were seen in patients with irAEs versus those withoutKhan et al28
FractalkineMelanoma147Anti-PD-1±anti-CTLA-4Fractalkine was significantly upregulated at baseline and early during treatment in severe irAEs and was integrated into the CYTOX (cytokine toxicity) score to predict severe irAE developmentLim et al27
  • BALF, bronchoalveolar lavage fluid; CIP, checkpoint inhibitor pneumonitis; CTLA-4, cytotoxic T lymphocyte protein 4; CYTOX, cytokine toxicity; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-α, interferon alpha; IL, interleukin; irAE, immune-related adverse event; NSCLC, non-small cell lung cancer; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1.