HLA-A*0201+ Plasmacytoid Dendritic Cells Provide a Cell-Based Immunotherapy for Melanoma Patients Caroline Aspord, Marie-Therese Leccia, Dimitri Salameire,

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Presentation transcript:

HLA-A*0201+ Plasmacytoid Dendritic Cells Provide a Cell-Based Immunotherapy for Melanoma Patients Caroline Aspord, Marie-Therese Leccia, Dimitri Salameire, David Laurin, Laurence Chaperot, Julie Charles, Joel Plumas Journal of Investigative Dermatology Volume 132, Issue 10, Pages 2395-2406 (October 2012) DOI: 10.1038/jid.2012.152 Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 The HLA-A*0201+ plasmacytoid dendritic cell (pDC) line loaded with melanoma-derived peptides induces multi-specific T-cell responses ex vivo from peripheral blood mononuclear cells (PBMCs) from stage I–IV melanoma patients. PBMCs obtained from stage I–IV HLA-A*0201+ melanoma patients (n=16) were cocultured with irradiated pDCs loaded with (a, c) one or (b, c) a mixture (mix) of peptides from among MelA-, gp100-, tyrosinase-, and MAGE-A3-derived HLA-A*0201-restricted peptides. Cultures were restimulated weekly in the presence of IL2. T cells were tetramer labeled at days 0, 7, 14, and 20 of culture to determine the percentage of specific cells. (a, b) Representative dotplots for each tumor antigen (gated on CD8+ T cells). (c) Percentages of tumor-specific T cells obtained initially and at different culture time points for 16 patients. d, day. Journal of Investigative Dermatology 2012 132, 2395-2406DOI: (10.1038/jid.2012.152) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 The HLA-A*0201+ plasmacytoid dendritic cell (pDC) line loaded with melanoma-derived peptides induces multi-specific T-cell responses ex vivo from tumor-infiltrating lymphocytes (TILs) from stage III to IV melanoma patients. TILs obtained from stage III to IV HLA-A*0201+ melanoma patients (n=17) were cocultured with irradiated pDCs loaded with (a, c) one or (b, c) a mixture (mix) of peptides from among MelA-, gp100-, tyrosinase-, and MAGE-A3-derived HLA-A*0201-restricted peptides. Cultures were restimulated weekly in the presence of IL2. T cells were tetramer-labeled at days 0, 7, 14, and 20 of culture to determine the percentage of specific cells. (a, b) Representative dotplots for each tumor antigen (gated on CD8+ T cells). (c) Percentages of tumor-specific T cells at different culture time points for 18 patients. d, day. Journal of Investigative Dermatology 2012 132, 2395-2406DOI: (10.1038/jid.2012.152) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Melanoma patients’ response to the plasmacytoid dendritic cell (pDC) strategy and immune score. (a) Percentage of patients responding to the pDC stimulation for each tumor antigen (16 peripheral blood mononuclear cell (PBMC), 18 tumor-infiltrating lymphocytes (TIL)). (b) An immune score was defined based on the patients’ ability to respond to one (score 1), two (score 2), three (score 3), or four (score 4) antigens. Percentage of patients for each score, after stimulation with pDCs loaded with either a single peptide or the four-peptide mixture (16 PBMC, 18 TIL). Journal of Investigative Dermatology 2012 132, 2395-2406DOI: (10.1038/jid.2012.152) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Tumor-specific T cells primed by peptide-loaded plasmacytoid dendritic cells (pDCs) secrete IFNγ and express CD107 on the surface upon specific restimulation. (a, b) Peripheral blood mononuclear cells (PBMCs) or (c–f) tumor-infiltrating lymphocytes (TILs) were cocultured with irradiated pDCs loaded with a single peptide or a mixture of the MelA-, GP100-, tyrosinase-, and MAGE-A3-derived HLA-A*0201-restricted peptides and restimulated weekly in the presence of IL2. Cells were tetramer labeled and restimulated with T2 cells pulsed with a relevant or control peptide. (a–d) IFNγ production was assessed by intracellular staining. CD107 expression was evaluated by adding anti-CD107a+b antibodies during restimulation. (a, c, e) Representative dotplots gated on CD8+ T cells (left panels) and tetramer+ CD8+ T cells (right panels). (b, d) Percent IFNγ+ tumor-specific T cells. (f) Percent CD107+ tumor-specific T cells. Journal of Investigative Dermatology 2012 132, 2395-2406DOI: (10.1038/jid.2012.152) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Tumor-specific T cells elicited by plasmacytoid dendritic cells (pDCs) from melanoma patients’ peripheral blood mononuclear cells (PBMCs) are highly cytotoxic. T cells induced from melanoma patients’ PBMCs by peptide-loaded pDCs were purified and used as effectors in a 51Cr-release assay. (a) Representative cytotoxicity assays on peptide-loaded T2 cells upon stimulation with single peptide–loaded pDCs. (b) Representative cytotoxicity assays on allogeneic melanoma tumor cells upon stimulation with pDCs loaded with MelA (left panel) or the four-peptide mixture (mix; right panel). (c) Killing of peptide-loaded T2 cells obtained with T cells specific to the corresponding peptide (left, single peptide, n=23; right, four-peptide mix, n=15). (d) Killing of allogeneic melanoma tumor cells obtained with PBMCs after stimulation with pDCs loaded with the four-peptide mixture; patients responding to tyrosinase were excluded (n=11). Journal of Investigative Dermatology 2012 132, 2395-2406DOI: (10.1038/jid.2012.152) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Tumor-specific T cells elicited by plasmacytoid dendritic cells (pDCs) from melanoma patients’ tumor-infiltrating lymphocytes (TILs) are highly cytotoxic and lyse autologous melanoma tumor cells. Unstimulated TILs (TIL day (d)0) or T cells induced from TILs by peptide-loaded pDCs were used as effectors in a 51Cr-release assay. (a) Representative cytotoxicity toward peptide-loaded T2 cells obtained with TILs responding to the antigens indicated. Representative cytotoxicity assays on (b, d) allogeneic or (c, e) autologous melanoma cells obtained with unstimulated TILs or TILs stimulated with pDCs loaded with (b, c) a single peptide or (d, e) the four-peptide mixture. (f) Percentage of cytotoxicity toward allogeneic (upper panels) or autologous melanoma cells and corresponding CD45+ cells (lower panels) obtained with unstimulated TILs or TILs stimulated with pDCs loaded with a single peptide or the four-peptide mixture. Journal of Investigative Dermatology 2012 132, 2395-2406DOI: (10.1038/jid.2012.152) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Tumor-specific T cells elicited by plasmacytoid dendritic cells (pDCs) from melanoma patients’ tumor-infiltrating lymphocytes (TILs) are highly cytotoxic and lyse autologous melanoma tumor cells. Unstimulated TILs (TIL day (d)0) or T cells induced from TILs by peptide-loaded pDCs were used as effectors in a 51Cr-release assay. (a) Representative cytotoxicity toward peptide-loaded T2 cells obtained with TILs responding to the antigens indicated. Representative cytotoxicity assays on (b, d) allogeneic or (c, e) autologous melanoma cells obtained with unstimulated TILs or TILs stimulated with pDCs loaded with (b, c) a single peptide or (d, e) the four-peptide mixture. (f) Percentage of cytotoxicity toward allogeneic (upper panels) or autologous melanoma cells and corresponding CD45+ cells (lower panels) obtained with unstimulated TILs or TILs stimulated with pDCs loaded with a single peptide or the four-peptide mixture. Journal of Investigative Dermatology 2012 132, 2395-2406DOI: (10.1038/jid.2012.152) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions