Multifunctionality of CD8+ T cells and PD-L1 expression as a biomarker of anti-PD-1 antibody efficacy in advanced melanoma

Keiko Manabe, Osamu Yamasaki, Yuki Nakagawa, Tomoko Miyake, Heiichiro Udono, Shin Morizane

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Anti-programmed cell death protein-1 (PD-1) antibodies have become a standard treatment for advanced melanoma. However, a predictive biomarker for assessing the efficacy of anti-PD-1 antibodies has not been identified. In cancer, CD8+ T cells specific for tumor antigens undergo repeated T-cell receptor stimulation due to the persistence of cancer cells and gradually lose their ability to secrete interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). We aimed to evaluate multi-cytokine production and immune exhaustion of peripheral CD8+ T cells in melanoma patients treated with anti-PD-1 antibodies. Twenty-four melanoma patients treated with nivolumab were included. Effector cytokine production (IL-2, TNF-α, and IFN-γ) and expression of an exhaustion marker (PD-1) in patients’ CD8+ cells were analyzed with flow cytometry. The relationships between parameters such as the neutrophil-to-lymphocyte ratio (NLR) and clinical response to nivolumab were examined. Immunohistochemistry for programmed death-ligand 1 (PD-L1) expression in tumor cells and tumor-infiltrating lymphocytes (TILs) and analysis of their association with clinical response were performed. The clinical response rate to nivolumab was 29%. Regarding TILs, NLR, and several other parameters, no significant difference was found between responders and non-responders. The responder group showed an increase in the percentage of PD-1+CD8+/TNF-α+IFN-γ+ or PD-1+CD8+/IFN-γ+IL-2+TNF-α+ T cells compared to non-responders. Positivity for PD-L1 expression was significantly higher in the responder group than the non-responder group. In advanced melanoma, the percentage of multifunctional CD8+PD-1+ T cells and PD-L1 expression in the tumors may be a biomarker for a good response to anti-PD-1 antibody monotherapy.

Original languageEnglish
Pages (from-to)1186-1192
Number of pages7
JournalJournal of Dermatology
Issue number8
Publication statusPublished - Aug 2021


  • PD-L1 expression
  • biomarker
  • immune checkpoint inhibitor
  • immune exhaustion
  • melanoma
  • nivolumab

ASJC Scopus subject areas

  • Dermatology


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