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

J Immunol. 2003 Oct 1;171(7):3467-74. doi: 10.4049/jimmunol.171.7.3467.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • 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