Combination of host immune metabolic biomarkers for the PD-1 blockade cancer immunotherapy

JCI Insight. 2020 Jan 30;5(2):e133501. doi: 10.1172/jci.insight.133501.


BACKGROUNDCurrent clinical biomarkers for the programmed cell death 1 (PD-1) blockade therapy are insufficient because they rely only on the tumor properties, such as programmed cell death ligand 1 expression frequency and tumor mutation burden. Identifying reliable, responsive biomarkers based on the host immunity is necessary to improve the predictive values.METHODSWe investigated levels of plasma metabolites and T cell properties, including energy metabolism markers, in the blood of patients with non-small cell lung cancer before and after treatment with nivolumab (n = 55). Predictive values of combination markers statistically selected were evaluated by cross-validation and linear discriminant analysis on discovery and validation cohorts, respectively. Correlation between plasma metabolites and T cell markers was investigated.RESULTSThe 4 metabolites derived from the microbiome (hippuric acid), fatty acid oxidation (butyrylcarnitine), and redox (cystine and glutathione disulfide) provided high response probability (AUC = 0.91). Similarly, a combination of 4 T cell markers, those related to mitochondrial activation (PPARγ coactivator 1 expression and ROS), and the frequencies of CD8+PD-1hi and CD4+ T cells demonstrated even higher prediction value (AUC = 0.96). Among the pool of selected markers, the 4 T cell markers were exclusively selected as the highest predictive combination, probably because of their linkage to the abovementioned metabolite markers. In a prospective validation set (n = 24), these 4 cellular markers showed a high accuracy rate for clinical responses of patients (AUC = 0.92).CONCLUSIONCombination of biomarkers reflecting host immune activity is quite valuable for responder prediction.FUNDINGAMED under grant numbers 18cm0106302h0003, 18gm0710012h0105, and 18lk1403006h0002; the Tang Prize Foundation; and JSPS KAKENHI grant numbers JP16H06149, 17K19593, and 19K17673.

Keywords: Cancer immunotherapy; Immunology; Oncology; T cells.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Immunological / pharmacology*
  • Antineoplastic Agents, Immunological / therapeutic use
  • Biomarkers, Tumor / immunology*
  • Carcinoma, Non-Small-Cell Lung
  • Carnitine / analogs & derivatives
  • Drug Therapy, Combination
  • Energy Metabolism
  • Female
  • Glutathione Disulfide
  • Hippurates
  • Humans
  • Immunotherapy / methods*
  • Lung Neoplasms
  • Male
  • Microbiota
  • Middle Aged
  • Nivolumab / pharmacology*
  • Nivolumab / therapeutic use
  • Programmed Cell Death 1 Receptor / drug effects*
  • Programmed Cell Death 1 Receptor / immunology*
  • Programmed Cell Death 1 Receptor / metabolism
  • Prospective Studies


  • Antineoplastic Agents, Immunological
  • Biomarkers, Tumor
  • Hippurates
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • butyrylcarnitine
  • Nivolumab
  • Carnitine
  • hippuric acid
  • Glutathione Disulfide