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

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. 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. 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. 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.

Tjin EP ，Konijnenberg D ，Krebbers G ，Mallo H ，Drijfhout JW ，Franken KL ，van der Horst CM ，Bos JD ，Nieweg OE ，Kroon BB ，Haanen JB ，Melief CJ ，Vyth-Dreese FA ，Luiten RM ... -  《-》

Lack of terminally differentiated tumor-specific CD8+ T cells at tumor site in spite of antitumor immunity to self-antigens in human metastatic melanoma.

Mortarini R ，Piris A ，Maurichi A ，Molla A ，Bersani I ，Bono A ，Bartoli C ，Santinami M ，Lombardo C ，Ravagnani F ，Cascinelli N ，Parmiani G ，Anichini A ... -  《CANCER RESEARCH》

Melanocyte-specific immune response in a patient with multiple regressing nevi and a history of melanoma.

Speeckaert R ，van Geel N ，Luiten RM ，van Gele M ，Speeckaert M ，Lambert J ，Vermaelen K ，Tjin EP ，Brochez L ... -  《-》

Simultaneous generation of CD8+ and CD4+ melanoma-reactive T cells by retroviral-mediated transfer of a single T-cell receptor.

Roszkowski JJ ，Lyons GE ，Kast WM ，Yee C ，Van Besien K ，Nishimura MI ... -  《CANCER RESEARCH》

Induction of tumor-reactive CTL from peripheral blood and tumor-infiltrating lymphocytes of melanoma patients by in vitro stimulation with an immunodominant peptide of the human melanoma antigen MART-1.

Rivoltini L ，Kawakami Y ，Sakaguchi K ，Southwood S ，Sette A ，Robbins PF ，Marincola FM ，Salgaller ML ，Yannelli JR ，Appella E ... -  《JOURNAL OF IMMUNOLOGY》