T-cell immune function in tumor, skin, and peripheral blood of advanced stage melanoma patients: implications for immunotherapy

Clin Cancer Res. 2011 Sep 1;17(17):5736-47. doi: 10.1158/1078-0432.CCR-11-0230. Epub 2011 Jul 12.

Abstract

Purpose: To predict the potential antitumor effect of antigen-specific T cells in melanoma patients, we investigated T-cell effector function in relation to tumor-escape mechanisms.

Experimental design: CD8(+) T cells isolated from tumor, adjacent normal skin, and peripheral blood of 17 HLA-A2(+) patients with advanced-stage melanoma were analyzed for their antigen specificity and effector function against melanocyte differentiation antigens MART-1, gp100, and tyrosinase by using HLA-A2/peptide tetramers and functional assays. In addition, the presence of tumor-escape mechanisms PD-L1/PD-1 pathway, FoxP3 and loss of HLA or melanocyte differentiation antigens, both required for tumor cell recognition and killing, were studied.

Results: Higher percentages of melanocyte antigen-specific CD8(+) T cells were found in the melanoma tissues as compared with adjacent normal skin and peripheral blood. Functional analysis revealed 2 important findings: (i) in 5 of 17 patients, we found cytokine production after specific peptide stimulation by tumor-infiltrating lymphocytes (TIL), not by autologous peripheral blood lymphocytes (PBL); (ii) CD8(+) T cells from 7 of 17 patients did not produce cytokines after specific stimulation, which corresponded with significant loss of tumor HLA-A2 expression. The presence of other tumor-escape mechanisms did not correlate to T-cell function.

Conclusions: Our data show that functional T-cell responses could be missed when only PBL and not TIL are evaluated, emphasizing the importance of TIL analysis for immunomonitoring. Furthermore, loss of tumor HLA-A2 may explain the lack of T-cell functionality. These findings have important implications for selecting melanoma patients who may benefit from immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • B7-H1 Antigen / biosynthesis
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Cytotoxicity, Immunologic
  • Female
  • Forkhead Transcription Factors / biosynthesis
  • HLA-A2 Antigen / biosynthesis
  • HLA-A2 Antigen / immunology
  • Humans
  • Immunotherapy*
  • Lymphocyte Activation
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • MART-1 Antigen / immunology
  • Male
  • Melanoma / blood
  • Melanoma / immunology*
  • Melanoma / pathology
  • Melanoma / therapy
  • Middle Aged
  • Monophenol Monooxygenase / immunology
  • Skin / immunology*
  • Tumor Escape
  • gp100 Melanoma Antigen / immunology

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • HLA-A2 Antigen
  • MART-1 Antigen
  • gp100 Melanoma Antigen
  • Monophenol Monooxygenase