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CD4-Dependent Potentiation of a High Molecular Weight-Melanoma-Associated Antigen-Specific CTL Response Elicited in HLA-A2/K^b Transgenic Mice¹

Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263

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.

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