High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade

Nat Med. 2020 May;26(5):693-698. doi: 10.1038/s41591-020-0860-1. Epub 2020 May 11.


Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade 1, this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8+ T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antineoplastic Agents, Immunological / therapeutic use*
  • B7-H1 Antigen / antagonists & inhibitors*
  • B7-H1 Antigen / immunology
  • Biomarkers, Pharmacological / blood
  • Biomarkers, Pharmacological / metabolism
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Renal Cell / diagnosis
  • Carcinoma, Renal Cell / drug therapy
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / mortality
  • Carcinoma, Transitional Cell / diagnosis
  • Carcinoma, Transitional Cell / drug therapy
  • Carcinoma, Transitional Cell / metabolism
  • Carcinoma, Transitional Cell / mortality
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Interleukin-8 / blood
  • Interleukin-8 / metabolism*
  • Kidney Neoplasms / diagnosis
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / mortality
  • Male
  • Neoplasms / diagnosis*
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / mortality
  • Prognosis
  • Survival Analysis
  • Treatment Failure
  • Urologic Neoplasms / diagnosis
  • Urologic Neoplasms / drug therapy
  • Urologic Neoplasms / metabolism
  • Urologic Neoplasms / mortality


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • Biomarkers, Pharmacological
  • Biomarkers, Tumor
  • CD274 protein, human
  • Interleukin-8
  • atezolizumab