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

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-gamma 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-A(27-35) in three of five HLA-A*0201 melanoma patients, and of CEA(571-579) and EpCAM(263-271) 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.

• Authors: 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
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 171 Issue 7 Pg. 3467-74 (Oct 01 2003) ISSN: 0022-1767 [Print] United States
• PMID: 14500642 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• Epitopes, T-Lymphocyte
• HLA-A Antigens
• HLA-A*02:01 antigen
• HLA-A2 Antigen
• Heat-Shock Proteins
• Peptide Fragments
• sarcoma glycoprotein gp96 rejection antigens

Topics

• Antigen Presentation
• Antigens, Neoplasm (immunology, metabolism, physiology)
• CD8-Positive T-Lymphocytes (immunology, pathology)
• Cancer Vaccines (administration & dosage, immunology)
• Cell Division (immunology)
• Cell Line, Tumor
• Clone Cells
• Colonic Neoplasms (immunology, pathology)
• Epitopes, T-Lymphocyte (immunology)
• HLA-A Antigens (immunology)
• HLA-A2 Antigen
• Heat-Shock Proteins (immunology, metabolism, physiology)
• Humans
• Lymphocyte Activation (immunology)
• Lymphocyte Count
• Melanoma (immunology, pathology)
• Peptide Fragments (immunology, metabolism)
• T-Lymphocyte Subsets (immunology, pathology)
• Up-Regulation (immunology)