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

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.

• Authors: Esther P M Tjin, Debby Konijnenberg, Gabrielle Krebbers, Henk Mallo, Jan W Drijfhout, Kees L M C Franken, Chantal M A M van der Horst, Jan D Bos, Omgo E Nieweg, Bin B R Kroon, John B A G Haanen, Cornelis J M Melief, Florry A Vyth-Dreese, Rosalie M Luiten
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 17 Pg. 5736-47 (Sep 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21750202 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

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

Topics

• 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, immunology)
• Humans
• Immunotherapy
• Lymphocyte Activation
• Lymphocytes, Tumor-Infiltrating (immunology)
• MART-1 Antigen (immunology)
• Male
• Melanoma (blood, immunology, pathology, therapy)
• Middle Aged
• Monophenol Monooxygenase (immunology)
• Skin (immunology)
• Tumor Escape
• gp100 Melanoma Antigen (immunology)