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Antibody and CD8⁺ T Cell Responses against HER2/neu Required for Tumor Eradication after DNA Immunization with a Flt-3 Ligand Fusion Vaccine

Authors' Affiliations: ¹ Swim Across America Laboratory. Memorial Sloan-Kettering Cancer Center, New York, New York; and ² Unit of Translational Medicine. University of Camerino, Camerino (MC), Italy

Requests for reprints: Polly D. Gregor, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 646-888-2545; Fax: 646-422-0453; E-mail: gregorp{at}mskcc.org.

Purpose: HER2/neu is frequently overexpressed in breast cancer. In a mouse model, vaccination with HER2/neu DNA elicits antibodies that confer partial protection against tumor challenge.

Experimental Design: To enhance antitumor immunity, we fused cDNA encoding Flt-3 ligand (FL) to the rat HER2/neu extracellular domain (neu), generating a chimeric FLneu molecule. FLneu and neu DNA vaccines were compared for immunogenicity and their ability to protect mice from tumor challenge.

Results: The neu vaccine generated a HER2/neu-specific antibody response. In contrast, vaccination with FLneu induced CD8⁺ T cells specific for HER2/neu but a negligible anti-HER2/neu antibody response. The switch from an antibody-mediated to T cell–mediated response was due to different intracellular localization of neu and FLneu. Although the neu protein was secreted, the FLneu protein was retained inside the cell, co-localizing with the endoplasmic reticulum, facilitating processing and presentation to T cells. The neu and FLneu vaccines individually conferred only weak tumor immunity. However, efficient tumor rejection was seen when neu and FLneu were combined, inducing both strong anti-HER2/neu-specific antibody and T cell responses. Adoptive transfer of both immune CD8⁺ T cells and immune sera from immunized mice was required to confer tumor immunity in naïve hosts.

Conclusions: These results show that active induction of both humoral and cellular immunity to HER2/neu is required for efficient tumor protection, and that neither response alone is sufficient.