Progressive upregulation of PD-1 in primary and metastatic melanomas associated with blunted TCR signaling in infiltrating T lymphocytes

J Invest Dermatol. 2011 Jun;131(6):1300-7. doi: 10.1038/jid.2011.30. Epub 2011 Feb 24.


Programmed death-1 (PD-1) is involved in T-cell tolerance to self-antigens. For some cancers, it has been suggested that the expression of a ligand of PD-1, namely PD-L1, could contribute to tumor escape from immune destruction. Nevertheless, the relationship between PD-1 expression on tumor-infiltrating T lymphocytes (TILs), disease stage, and TIL responsiveness is still poorly documented. In this study, we show that freshly isolated CD4(+) and CD8(+) TILs express substantial levels of PD-1 in primary melanomas. The expression of PD-1 was further increased at later stages in distant cutaneous metastases, especially on CD8(+) TILs. The expression of PD-1 ligands was frequent only in metastases, on both tumor cells and tumor-derived myeloid cells. TILs isolated from these cutaneous tumors are poorly reactive ex vivo, with blunted calcium response and IFN-γ production after TCR stimulation. Surprisingly, in distinct parts of a primary melanoma, either invasive or regressing, we show that TILs similarly express PD-1 and remain dysfunctional. The expressions of PD-1 and PD-L1 in metastatic melanoma lesions could be considered as witnesses of an unsuccessful anti-tumoral immune response, but the direct involvement of PD-1 in the severity of the disease, and the importance of TILs in tumor regression, remain to be established.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antigens, CD / analysis
  • Antigens, CD / physiology*
  • Apoptosis Regulatory Proteins / analysis
  • Apoptosis Regulatory Proteins / physiology*
  • B7-1 Antigen / analysis
  • B7-H1 Antigen
  • Female
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Male
  • Melanoma / immunology*
  • Melanoma / secondary
  • Middle Aged
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • Prospective Studies
  • Receptors, Antigen, T-Cell / physiology*
  • Signal Transduction / physiology*
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / pathology
  • T-Lymphocytes / immunology*


  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • B7-1 Antigen
  • B7-H1 Antigen
  • CD274 protein, human
  • PDCD1 protein, human
  • PDCD1LG2 protein, human
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell