Inflammatory markers in autoimmunity induced by checkpoint inhibitors

J Cancer Res Clin Oncol. 2021 Jun;147(6):1623-1630. doi: 10.1007/s00432-021-03550-5. Epub 2021 Apr 10.


Purpose: Immune checkpoint inhibitors (ICI) are highly effective in several cancer entities, but also invoke a variety of immune-related adverse events (irAE). These are mostly reversible, but can be life-threatening or even fatal. Currently, the pathogenesis is not fully understood, but crucial for effective treatment. Prediction and early detection of irAE could be facilitated and treatment optimized if relevant biomarkers and effector mechanisms were better characterized.

Methods: This study included a total of 45 irAE in patients with metastatic melanoma who were treated with ICI. All patients underwent a complete work-up with exclusion of other causes. Longitudinal blood samples were analyzed for a panel of soluble markers and compared to baseline and to patients who did not experience any irAE. Measurements included LDH, interleukin (IL)-6, IL-1β, IL-17, C-reactive protein (CRP) and tumor necrosis factor (TNF)-alpha as well as tumor markers S100 and melanoma inhibitory activity (MIA).

Results: During the early onset of irAE increases in serum IL-6 (from mean 24.4 pg/ml at baseline to 51.0 pg/ml; p = 0.003) and CRP (from mean 7.0 mg/l at baseline to 17.7 mg/l; p = 0.001) and a decrease in MIA (from mean 5.4 pg/ml at baseline to 4.8 pg/ml; p = 0.035) were detected. No changes in IL-17 were noted. These effects were observed for irAE of different organ systems.

Conclusion: Increases of a combination of IL-6 and CRP serum levels can be used for the early detection of irAE and tailored management. Interestingly, changes in MIA serum levels also correlate with irAE onset.

Keywords: Cytokines; Immune checkpoint inhibitors; Immune-related adverse events; Melanoma.

MeSH terms

  • Adult
  • Autoimmunity / drug effects*
  • Autoimmunity / genetics
  • Autoimmunity / immunology
  • Biomarkers, Tumor / blood*
  • Biomarkers, Tumor / genetics
  • Case-Control Studies
  • Cohort Studies
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / chemically induced
  • Diabetes Mellitus, Type 1 / immunology
  • Endocrine System Diseases / blood
  • Endocrine System Diseases / chemically induced
  • Endocrine System Diseases / immunology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / immunology
  • Germany
  • Humans
  • Immune Checkpoint Inhibitors / adverse effects*
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Inflammation / blood*
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Inflammation / immunology
  • Male
  • Melanoma / blood
  • Melanoma / drug therapy
  • Melanoma / genetics
  • Melanoma / pathology
  • Neoplasm Metastasis
  • Skin Neoplasms / blood
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology
  • Uveal Neoplasms / blood
  • Uveal Neoplasms / drug therapy
  • Uveal Neoplasms / genetics
  • Uveal Neoplasms / pathology


  • Biomarkers, Tumor
  • Immune Checkpoint Inhibitors

Supplementary concepts

  • Melanoma, Cutaneous Malignant
  • Uveal melanoma