Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired

Blood. 2009 Aug 20;114(8):1537-44. doi: 10.1182/blood-2008-12-195792. Epub 2009 May 7.


Tumor antigen-specific T cells are found within melanomas, yet tumors continue to grow. Although the tumor microenvironment is thought to influence the suppression of tumor-reactive T cells, the underlying mechanisms for this T-cell dysfunction are not clear. Here, we report that the majority of tumor infiltrating T lymphocytes (TIL), including MART-1/Melan-A melanoma antigen-specific CD8 T cells, predominantly expressed PD-1, in contrast to T cells in normal tissues and peripheral blood T lymphocytes (PBL). PD-1(+) TIL expressed CTLA-4 and Ki-67, markers that were not expressed by PD-1(-) TIL and T cells in the normal tissues and PBL. Moreover, PD-1(+) TIL were primarily HLA-DR(+) and CD127(-), in contrast to PD-1(-) TIL. Effector cytokine production by PD-1(+) TIL was impaired compared with PD-1(-) TIL and PBL. Collectively, the phenotypic and functional characterizations of TIL revealed a significantly higher frequency and level of PD-1 expression on TIL compared with normal tissue T-cell infiltrates and PBL, and PD-1 expression correlated with an exhausted phenotype and impaired effector function. These findings suggest that the tumor microenvironment can lead to up-regulation of PD-1 on tumor-reactive T cells and contribute to impaired antitumor immune responses.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antigens, CD / metabolism*
  • Antigens, Neoplasm / metabolism
  • Apoptosis Regulatory Proteins / metabolism*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / physiology*
  • Child
  • Cytotoxicity, Immunologic / physiology
  • Female
  • Humans
  • Lymphocyte Activation / physiology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Lymphocytes, Tumor-Infiltrating / physiology*
  • MART-1 Antigen
  • Male
  • Melanoma / blood
  • Melanoma / immunology*
  • Melanoma / metabolism
  • Melanoma / physiopathology
  • Middle Aged
  • Neoplasm Proteins / metabolism
  • Programmed Cell Death 1 Receptor
  • Tumor Escape / immunology
  • Up-Regulation
  • Young Adult


  • Antigens, CD
  • Antigens, Neoplasm
  • Apoptosis Regulatory Proteins
  • MART-1 Antigen
  • MLANA protein, human
  • Neoplasm Proteins
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor