Human tumor-derived heat shock protein 96 mediates in vitro activation and in vivo expansion of melanoma- and colon carcinoma-specific T cells

Licia Rivoltini, Chiara Castelli, Matteo Carrabba, Vincenzo Mazzaferro, Lorenzo Pilla, Veronica Huber, Jorgelina Coppa, Gianfrancesco Gallino, Carmen Scheibenbogen, Paola Squarcina, Agata Cova, Roberto Camerini, Jonathan J. Lewis, Pramod K. Srivastava, Giorgio Parmiani

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Abstract

Heat shock proteins (hsp) 96 play an essential role in protein metabolism and exert stimulatory activities on innate and adaptive immunity. Vaccination with tumor-derived hsp96 induces CD8+ T cell-mediated tumor regressions in different animal models. In this study, we show that hsp96 purified from human melanoma or colon carcinoma activate tumor- and Ag-specific T cells in vitro and expand them in vivo. HLA-A*0201-restricted CD8 + T cells recognizing Ags expressed in human melanoma (melanoma Ag recognized by T cell-1 (MART-1)/melanoma Ag A (Melan-A)) or colon carcinoma (carcinoembryonic Ag (CEA)/epithelial cell adhesion molecule (EpCAM)) were triggered to release IFN-γ and to mediate cytotoxic activity by HLA-A*0201-matched APCs pulsed with hsp96 purified from tumor cells expressing the relevant Ag. Such activation occurred in class I HLA-restricted fashion and appeared to be significantly higher than that achieved by direct peptide loading. Immunization with autologous tumor-derived hsp96 induced a significant increase in the recognition of MART-1/Melan-A27-35 in three of five HLA-A*0201 melanoma patients, and of CEA571-579 and EpCAM263-271 in two of five HLA-A*0201 colon carcinoma patients, respectively, as detected by ELISPOT and HLA/tetramer staining. These increments in Ag-specific T cell responses were associated with a favorable disease course after hsp96 vaccination. Altogether, these data provide evidence that hsp96 derived from human tumors can present antigenic peptides to CD8 + T cells and activate them both in vitro and in vivo, thus representing an important tool for vaccination in cancer patients.

Original languageEnglish
Pages (from-to)3467-3474
Number of pages8
JournalJournal of Immunology
Volume171
Issue number7
Publication statusPublished - Oct 1 2003

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ASJC Scopus subject areas

  • Immunology

Cite this

Rivoltini, L., Castelli, C., Carrabba, M., Mazzaferro, V., Pilla, L., Huber, V., Coppa, J., Gallino, G., Scheibenbogen, C., Squarcina, P., Cova, A., Camerini, R., Lewis, J. J., Srivastava, P. K., & Parmiani, G. (2003). Human tumor-derived heat shock protein 96 mediates in vitro activation and in vivo expansion of melanoma- and colon carcinoma-specific T cells. Journal of Immunology, 171(7), 3467-3474.