Induction of myeloma-specific cytotoxic T cells using dendritic cells transfected with tumor-derived RNA by Caterina Milazzo, Volker L. Reichardt, Martin.

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Presentation transcript:

Induction of myeloma-specific cytotoxic T cells using dendritic cells transfected with tumor-derived RNA by Caterina Milazzo, Volker L. Reichardt, Martin R. Müller, Frank Grünebach, and Peter Brossart Blood Volume 101(3):977-982 February 1, 2003 ©2003 by American Society of Hematology

Specific lysis of the LP-1 cell line by CTLs induced by DCs transfected with LP-1–derived RNA.DCs were generated from adherent PBMNCs of an HLA-A3/24, B62/50, Cw9/6 (panel A) and an HLA-A3/24, B35/60, Cw3/4 (panel B) buffy coat in RP-10 medium supplemented ... Specific lysis of the LP-1 cell line by CTLs induced by DCs transfected with LP-1–derived RNA.DCs were generated from adherent PBMNCs of an HLA-A3/24, B62/50, Cw9/6 (panel A) and an HLA-A3/24, B35/60, Cw3/4 (panel B) buffy coat in RP-10 medium supplemented with GM-CSF and IL-4 and electroporated on day 6 with total RNA of the LP-1 cell line. After a 24-hour culture with TNF-α as maturation stimulus, the transfected DCs were used for the induction of CTLs. At 5 days after the first restimulation, the cytolytic activity of the cells was determined in a standard51Cr-release assay, with the use of the myeloma cell lines LP-1 (HLA-A3/24, B7/18, Cw7,−) and U266 (HLA-A2/3, B7/40, Cw3/7); the breast cancer cell line MCF-7 (HLA-A2,−, B18/44, Cw5,−); the ovarian cancer cell line SK-OV-3 (HLA-A3/68, B18/35); the renal cancer cell line A498 (HLA-A2,−, B8,−); and the EBV-immortalized B-cell line Croft (HLA-A2,−, B7/8, Cw7,−) (loaded with the HIV peptide) as targets. Caterina Milazzo et al. Blood 2003;101:977-982 ©2003 by American Society of Hematology

Cold-target inhibition results Cold-target inhibition results.Cold-target inhibition proves the specificity of the LP-1–specific CTLs. The myeloma cell line LP-1 was used as a target in a 51Cr-release assay. Cold-target inhibition results.Cold-target inhibition proves the specificity of the LP-1–specific CTLs. The myeloma cell line LP-1 was used as a target in a 51Cr-release assay. The antigen specificity of the CTLs was tested in the presence of unlabeled LP-1 or SK-OV-3 tumor cells as cold targets, with an inhibitor-target ratio of 20:1. Caterina Milazzo et al. Blood 2003;101:977-982 ©2003 by American Society of Hematology

Effect of anti–MHC class I antibodies on LP-1 lysis Effect of anti–MHC class I antibodies on LP-1 lysis.Lysis of the myeloma cell line LP-1 by CTLs induced with LP-1 total RNA is blocked by anti–MHC class I antibodies. Effect of anti–MHC class I antibodies on LP-1 lysis.Lysis of the myeloma cell line LP-1 by CTLs induced with LP-1 total RNA is blocked by anti–MHC class I antibodies. LP-1 cells were51Cr-labeled for 1 hour, washed, and then incubated for 30 minutes at 37°C with an anti–MHC class I antibody (clone W6/32) or with a mouse IgG isotype control antibody at a final concentration of 50 μg/mL and used as targets in a 51Cr-release assay. Caterina Milazzo et al. Blood 2003;101:977-982 ©2003 by American Society of Hematology

Idiotype nonspecificity of LP-1–specific CTLs Idiotype nonspecificity of LP-1–specific CTLs.DCs were generated from adherent PBMNCs of an HLA-A3/24, B44/60, Cw3/5 buffy coat in RP-10 medium supplemented with GM-CSF and IL-4. Idiotype nonspecificity of LP-1–specific CTLs.DCs were generated from adherent PBMNCs of an HLA-A3/24, B44/60, Cw3/5 buffy coat in RP-10 medium supplemented with GM-CSF and IL-4. On days 1 and 5, the isolated idiotype of the LP-1 cells was given to the culture at a final concentration of 50 μg/mL, before the addition of TNF-α on day 6. After a culture period of 7 days, the Id-pulsed DCs as well as LP-1 myeloma cells and natural killer (NK)–sensitive K562 cells were used as targets in a 51Cr-release assay. Autologous DCs were transfected with LP-1 total RNA or control RNA (EGFP IVT) on day 6 by electroporation and used on day 7 as additional control. Caterina Milazzo et al. Blood 2003;101:977-982 ©2003 by American Society of Hematology

Induction of specific lysis of the U266 cell line by CTLs by the use of U266 RNA–transfected DCs.Monocyte-derived DCs of an HLA-A2,−, B18/51, Cw7,− (panel A) and an HLA-A2/3, B35/8, Cw4,− (panel B) buffy coat, transfected with total RNA of the U266 cell lin... Induction of specific lysis of the U266 cell line by CTLs by the use of U266 RNA–transfected DCs.Monocyte-derived DCs of an HLA-A2,−, B18/51, Cw7,− (panel A) and an HLA-A2/3, B35/8, Cw4,− (panel B) buffy coat, transfected with total RNA of the U266 cell line, were used as antigen-presenting cells (APCs) for the induction of CTLs. Cytolytic activity of the CTLs was determined in a standard 51Cr-release assay on day 5 after the first restimulation. Myeloma cell lines LP-1 (HLA-A3/24, B7/18, Cw7,−) and U266 (HLA-A2/3, B7/40, Cw3/7) and the tumor cell lines MCF-7 (HLA-A2,−, B18/44, Cw5,−), SK-OV-3 (HLA-A3/68, B18/35), and A498 (HLA-A2,−, B8,−) were used as targets. Caterina Milazzo et al. Blood 2003;101:977-982 ©2003 by American Society of Hematology

Blockage of lysis of the myeloma cell line U266 by anti–MHC class I antibodies.For blocking experiments, 51Cr-labeled U266 tumor cells were incubated for 30 minutes with an anti–MHC class I antibody (clone W6/32) or a mouse IgG isotype control antibody at a... Blockage of lysis of the myeloma cell line U266 by anti–MHC class I antibodies.For blocking experiments, 51Cr-labeled U266 tumor cells were incubated for 30 minutes with an anti–MHC class I antibody (clone W6/32) or a mouse IgG isotype control antibody at a final concentration of 50 μg/mL. Caterina Milazzo et al. Blood 2003;101:977-982 ©2003 by American Society of Hematology

U266-specific CTL reactivity against the MUC1-derived peptide M1. 2 U266-specific CTL reactivity against the MUC1-derived peptide M1.2.To analyze the fine specificity of the U266-specific CTLs, Croft cells (EBV-immortalized B-cell line, MUC1−, HLA-A2+) were pulsed for 2 hours with 50 μg/mL MUC1-derived peptides M1.1 or M1.2... U266-specific CTL reactivity against the MUC1-derived peptide M1.2.To analyze the fine specificity of the U266-specific CTLs, Croft cells (EBV-immortalized B-cell line, MUC1−, HLA-A2+) were pulsed for 2 hours with 50 μg/mL MUC1-derived peptides M1.1 or M1.2, and used as target cells in a standard51Cr-release assay. As a negative control, Croft cells pulsed with the HIV peptide were used. Similar results were obtained in 2 separate experiments. Caterina Milazzo et al. Blood 2003;101:977-982 ©2003 by American Society of Hematology