Selection of CD8+PD-1+ lymphocytes in fresh human melanomas enriches for tumor-reactive T cells

J Immunother. Nov-Dec 2010;33(9):956-64. doi: 10.1097/CJI.0b013e3181fad2b0.

Abstract

CD8+ tumor-infiltrating lymphocytes (TILs) in human melanomas express high levels of PD-1 and are functionally impaired. However, adoptive cell therapy using in vitro-expanded TIL can be a highly effective therapy for patients with advanced melanoma. This discrepancy led us to further analyze the CD8+PD-1+ TILs. We found that the percentage of PD-1-expressing CD8+ T cells was higher in the tumor digests that generate tumor-reactive TILs after in vitro culture in interleukin-2 (P=0.0007). Also sorted and expanded CD8+PD-1+ T cells in tumor digests showed much higher tumor-specific interferon-γ production compared with CD8+PD-1⁻ T cells. These results suggested that tumor-specific CD8+ T cells in melanoma tumor digests are largely PD-1, and this population can recover function after culturing in interleukin-2. PD-1 has been reported as an inhibitory receptor on T cells. We found that the in vitro functional suppression of cultured-TILs from native levels of PD-L1 expression on melanomas was minimal, and moreover expression level of PD-1 on CD8+ tumor-specific TILs decreased during the culture. As a consequence, the PD-1 receptor can be a useful biomarker for enriching tumor-specific T cells from fresh melanomas.

MeSH terms

  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Antigens, CD / metabolism*
  • Antigens, Neoplasm / immunology
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / immunology
  • Apoptosis Regulatory Proteins / metabolism*
  • Biomarkers, Tumor / metabolism*
  • CD8-Positive T-Lymphocytes
  • Cell Proliferation
  • HLA-A2 Antigen / metabolism
  • Humans
  • Immunotherapy, Adoptive*
  • Interferon-gamma / metabolism
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism
  • Lymphocyte Activation
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Melanoma / immunology*
  • Melanoma / pathology
  • Programmed Cell Death 1 Receptor
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / pathology
  • Tumor Cells, Cultured

Substances

  • Antigens, CD
  • Antigens, Neoplasm
  • Apoptosis Regulatory Proteins
  • Biomarkers, Tumor
  • HLA-A2 Antigen
  • Interleukin-2
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma