TY - JOUR
T1 - Human tumor-derived heat shock protein 96 mediates in vitro activation and in vivo expansion of melanoma- and colon carcinoma-specific T cells
AU - Rivoltini, Licia
AU - Castelli, Chiara
AU - Carrabba, Matteo
AU - Mazzaferro, Vincenzo
AU - Pilla, Lorenzo
AU - Huber, Veronica
AU - Coppa, Jorgelina
AU - Gallino, Gianfrancesco
AU - Scheibenbogen, Carmen
AU - Squarcina, Paola
AU - Cova, Agata
AU - Camerini, Roberto
AU - Lewis, Jonathan J.
AU - Srivastava, Pramod K.
AU - Parmiani, Giorgio
PY - 2003/10/1
Y1 - 2003/10/1
N2 - 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.
AB - 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.
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M3 - Article
C2 - 14500642
AN - SCOPUS:0141955112
VL - 171
SP - 3467
EP - 3474
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 7
ER -