Inhibition of melanoma growth after treatment with dendritic cells in a Tyr-SV40E murine model requires CD4+ T cells but not CD8+ T cells.
Melanomas are promising targets for immunotherapy, as they express a number of tissue-specific antigens against which immune responses can be elicited. We have previously described transgenic mice in which malignant cutaneous melanomas are produced. The 1042 melanoma cell line, derived from a primary melanoma in one of these mice, was used here to generate tumours by subcutaneous inoculation in syngeneic animals. All mice injected with 1 x 10(6) cells of the 1042 cell line developed a tumour. CD4+ T cells, CD8+ T cells and macrophages infiltrated the tumours. Treatment with dendritic cells pulsed with peptides from melanogenic proteins slowed tumour growth and resulted in increased numbers of infiltrating lymphocytes and macrophages, expansion of CD4+ T cells specific for 1042 cell antigens, and increased levels of 1042-specific immunoglobulin G1 (IgG1) and IgM in serum. The frequency of cytotoxic T lymphocytes (CTLs) specific for the MART-1 melanocytic antigen did not increase after dendritic cell treatment. Indeed, the presence of CD8+ T cells was apparently not required for the anti-tumour effects: slowing of tumour growth was not abrogated in animals depleted of CD8+ T cells using antibodies, or in syngeneic CD8-/- animals. In contrast, treatment with dendritic cells + peptides was ineffective after depletion of CD4+ T cells and in syngeneic CD4-/- mice. This experimental system therefore provides an opportunity to investigate CD4-dependent anti-tumour effector mechanisms, and for studies designed to activate the quiescent CTLs which infiltrate melanomas.
Milling
Simon W F
SW
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USA. simon.milling@pathology.oxford.ac.uk
Sai
Tao
T
Silvers
Willys K
WK
Mintz
Beatrice
B
D000818:Animals; D000951:Antigens, Neoplasm; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000097:blood; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D058965:MART-1 Antigen; D008264:Macrophages; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014442:Monophenol Monooxygenase / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D013539:Simian virus 40 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic
D000951:Antigens, Neoplasm; D016207:Cytokines; D007074:Immunoglobulin G; D058965:MART-1 Antigen; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D014442:Monophenol Monooxygenase