Peripheral PD-1+CD56+ T-cell frequencies correlate with outcome in stage IV melanoma under PD-1 blockade

PLoS One. 2019 Aug 16;14(8):e0221301. doi: 10.1371/journal.pone.0221301. eCollection 2019.

Abstract

Immune checkpoint blockade with anti-PD-1 antibodies is showing great promise for patients with metastatic melanoma and other malignancies, but despite good responses by some patients who achieve partial or complete regression, many others still do not respond. Here, we sought peripheral blood T-cell biomarker candidates predicting treatment outcome in 75 stage IV melanoma patients treated with anti-PD-1 antibodies. We investigated associations with clinical response, progression-free survival (PFS) and overall survival (OS). Univariate analysis of potential biological confounders and known biomarkers, and a multivariate model, was used to determine statistical independence of associations between candidate biomarkers and clinical outcomes. We found that a lower than median frequency of peripheral PD-1+CD56+ T-cells was associated with longer OS (p = 0.004), PFS (p = 0.041) and superior clinical benefit (p = 0.009). However, neither frequencies of CD56-CD4+ nor CD56-CD8+ T-cells, nor of the PD-1+ fraction within the CD4 or CD8 subsets was associated with clinical outcome. In a multivariate model with known confounders and biomarkers only the M-category (HR, 3.11; p = 0.007) and the frequency of PD-1+CD56+ T-cells (HR, 2.39; p = 0.028) were identified as independent predictive factors for clinical outcome under PD-1 blockade. Thus, a lower than median frequency of peripheral blood PD-1+CD56+ T-cells prior to starting anti-PD-1 checkpoint blockade is associated with superior clinical response, longer PFS and OS of stage IV melanoma patients.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antineoplastic Agents, Immunological / therapeutic use*
  • CD56 Antigen / metabolism
  • Female
  • Follow-Up Studies
  • Humans
  • Lymphocyte Count
  • Male
  • Melanoma / blood
  • Melanoma / drug therapy*
  • Melanoma / mortality
  • Middle Aged
  • Neoplasm Staging
  • Nivolumab / therapeutic use
  • Prognosis
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / metabolism
  • Progression-Free Survival
  • Skin Neoplasms / blood
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / mortality
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • CD56 Antigen
  • NCAM1 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Nivolumab
  • pembrolizumab

Grant support

This work was partially funded by the Klaus Tschira Stiftung (00.316.2017; KWH & BW) [https://www.klaus-tschira-stiftung.de/], the Fortüne-program (F1261355; KWH) and the IZKF-program (E050005791; KWH) of the Medical Faculty of the University of Tübingen [https://www.medizin.uni-tuebingen.de/de/medizinische-fakultaet/forschung/interne-forschungsfrderung#junior_academy]. Contribution to publications costs derived from the German Research Council (DFG) and the Open Access Publishing Fund of the University of Tübingen (KWH) [https://uni-tuebingen.de/einrichtungen/universitaetsbibliothek/publizieren-forschen/open-access/open-access-publikationsfonds/]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.