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

• Hatae, Ryusuke

• Chamoto, Kenji

• Kim, Young Hak

• Sonomura, Kazuhiro

• Taneishi, Kei

• Kawaguchi, Shuji

• Yoshida, Hironori

• Ozasa, Hiroaki

• Sakamori, Yuichi

• Akrami, Maryam

• Fagarasan, Sidonia

• Masuda, Izuru

• Okuno, Yasushi

• Matsuda, Fumihiko

• Hirai, Toyohiro

• Honjo, Tasuku

Abstract

BACKGROUND. Current 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. METHODS. We 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. RESULTS. The 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). CONCLUSION. Combination of biomarkers reflecting host immune activity is quite valuable for responder prediction.

Journal

• JCI Insight

  JCI Insight 5 (2), e133501-, 2020-01-30

  American Society for Clinical Investigation

Keywords

• General Medicine

Details

• CRID: 1050283687642293632
• NII Article ID: 120006784459
• ISSN: 23793708
• DOI: 10.1172/jci.insight.133501
• HANDLE: 2433/245622
• Web Site: https://insight.jci.org/articles/view/133501/files/pdf
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN