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Hyperthermia Enhances CTL Cross-Priming¹

Hongzhen Shi^*, Tinghua Cao^*, John E. Connolly^*, Laurence Monnet^*, Lynda Bennett^*, Sylvie Chapel, Claude Bagnis, Patrice Mannoni, Jean Davoust^2,*, A. Karolina Palucka^3,* and Jacques Banchereau^3,*

^* Baylor Institute for Immunology Research, Dallas, TX 75204; and Etablissement Français du Sang Alpes Mediterranée, Marseille, France

Dendritic cells (DCs) loaded with killed allogeneic melanoma cells can cross-prime naive CD8⁺ T cells to differentiate into melanoma-specific CTLs in 3-wk cultures. In this study we show that DCs loaded with killed melanoma cells that were heated to 42°C before killing are more efficient in cross-priming of naive CD8⁺ T cells than DCs loaded with unheated killed melanoma cells. The enhanced cross-priming was demonstrated by several parameters: 1) induction of naive CD8⁺ T cell differentiation in 2-wk cultures, 2) enhanced killing of melanoma peptide-pulsed T2 cells, 3) enhanced killing of HLA-A*0201⁺ melanoma cells in a standard 4-h chromium release assay, and 4) enhanced capacity to prevent tumor growth in vitro in a tumor regression assay. Two mechanisms might explain the hyperthermia-induced enhanced cross-priming. First, heat-treated melanoma cells expressed increased levels of 70-kDa heat shock protein (HSP70), and enhanced cross-priming could be reproduced by overexpression of HSP70 in melanoma cells transduced with HSP70 encoding lentiviral vector. Second, hyperthermia resulted in the increased transcription of several tumor Ag-associated Ags, including MAGE-B3, -B4, -A8, and -A10. Thus, heat treatment of tumor cells permits enhanced cross-priming, possibly via up-regulation of both HSPs and tumor Ag expression.

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