CD4-dependent potentiation of a high molecular weight-melanoma-associated antigen-specific CTL response elicited in HLA-A2/Kb transgenic mice.
The human high m.w.-melanoma-associated Ag (HMW-MAA) is an attractive target for the immunotherapy of melanoma, due to its relatively high expression in a high percentage of melanoma lesions and its restricted distribution in normal tissues. Active immunization with HMW-MAA mimics has been previously shown to induce a HMW-MAA-specific, T cell-dependent Ab response associated with an apparent clinically beneficial effect in advanced melanoma patients. Although T cells play an important role in controlling tumor growth, only limited information is available to date about the induction of HMW-MAA-specific CTL. In this report, we show that immunization of HLA-A2/K(b) transgenic mice with HMW-MAA cDNA-transfected syngeneic dendritic cells elicited a CD8(+) CTL response specific for HMW-MAA peptides with HLA-A2 Ag-binding motifs. The elicited CTL lysed HLA-A2(+)HMW-MAA(+) melanoma cells in vitro, and mouse HLA-A2/K(b) cells pulsed with HMW-MAA-derived peptides in vitro and in vivo. Although this CTL response could be generated in the absence of CD4(+) T cell help, harnessing CD4(+) T cell help in a noncognate Ag-specific manner with the polyclonal activator staphylococcal enterotoxin A augmented the CTL response. These results imply that dendritic cell-based immunization, in combination with CD4(+) T cell help, represents an effective strategy to implement T cell-based immunotherapy targeting HMW-MAA in patients with HMW-MAA-bearing tumors.
Peng
Liaomin
L
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Ko
Eric
E
Luo
Wei
W
Wang
Xinhui
X
Shrikant
Protul A
PA
Ferrone
Soldano
S
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004768:Enterotoxins / Q000494:pharmacology; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation; D000099192:CD69 Antigens; D000099216:Chondroitin Sulfate Proteoglycan 4
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; D015704:CD4 Antigens; D004768:Enterotoxins; D015789:HLA-A2 Antigen; D007371:Interferon-gamma; D037181:Lectins, C-Type; D000099192:CD69 Antigens; D000099216:Chondroitin Sulfate Proteoglycan 4; C026066:enterotoxin A, Staphylococcal