Human heat shock protein 70 peptide complexes specifically activate antimelanoma T cells.

Members of the heat shock protein 70 (HSP70) family display a broad cellular localization and thus bind a repertoire of chaperoned peptides potentially derived from proteins of different cellular compartments. In this report, we show that HSP70 purified from human melanoma can activate T cells recognizing melanoma differentiation antigens in an antigen- and HLA class I-dependent fashion. HLA class I-restricted anti-melanoma T cells were susceptible to MHC-restricted, HSP70-dependent stimulation, indicating that HSP70 complexed peptides were able to gain access to the class I HLA presentation pathway. In addition, MHC matching between the melanoma cells used as a source of HSP and the responding T cells were not required, indicating that HSP70 activation may occur across MHC barriers. Besides the MHC-restricted and peptide-dependent activation pathway, HSP70 with no endogenous complexed peptides or HSP70 purified from antigen-negative cells was also able to induce IFN-gamma release by antimelanoma T cells by a MHC-independent mechanism. In this case, however, higher doses of HSP70 were required. The capacity to activate class I-restricted, antitumor T cells as well as antigen-presenting cells, together with the finding that the HSP70 chaperoned peptide repertoire includes melanoma-shared epitopes, holds promise for a HSP70-based cancer vaccine.

[1]  Stuart K. Calderwood,et al.  HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine , 2000, Nature Medicine.

[2]  G. Parmiani,et al.  T‐cell recognition of melanoma‐associated antigens , 2000 .

[3]  Nina Bhardwaj,et al.  Consequences of cell death: exposure to necrotic tumor cells , 2000 .

[4]  R. Jensen,et al.  Protein translocation: Is Hsp70 pulling my chain? , 1999, Current Biology.

[5]  R. Schekman,et al.  Protein Translocation How Hsp70 Pulls It Off , 1999, Cell.

[6]  B. Fleischer,et al.  In vivo and in vitro activation of T cells after administration of Ag-negative heat shock proteins. , 1999, Journal of immunology.

[7]  S. Rosenberg,et al.  A new era for cancer immunotherapy based on the genes that encode cancer antigens. , 1999, Immunity.

[8]  H. Rammensee,et al.  Stress proteins and immunity mediated by cytotoxic T lymphocytes. , 1999, Current opinion in immunology.

[9]  G. Parmiani,et al.  Novel HLA-Cw8-restricted T cell epitopes derived from tyrosinase-related protein-2 and gp100 melanoma antigens. , 1999, Journal of immunology.

[10]  P. Srivastava,et al.  Isolation of MHC class I-restricted tumor antigen peptide and its precursors associated with heat shock proteins hsp70, hsp90, and gp96. , 1999, Journal of immunology.

[11]  P. Coulie,et al.  Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE‐3 and presented by HLA‐A1 , 1999, International journal of cancer.

[12]  M. Lotze,et al.  Rapid extracellular degradation of synthetic class I peptides by human dendritic cells. , 1998, Journal of immunology.

[13]  P. Srivastava,et al.  Heat shock proteins come of age: primitive functions acquire new roles in an adaptive world. , 1998, Immunity.

[14]  A. Melcher,et al.  Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression , 1998, Nature Medicine.

[15]  M. Maio,et al.  Immunogenicity of the ALLAVGATK (gp10017 – 25) peptide in HLA‐A3.1 melanoma patients , 1998, European journal of immunology.

[16]  R. Welsh,et al.  Immunization with a Lymphocytic Choriomeningitis Virus Peptide Mixed with Heat Shock Protein 70 Results in Protective Antiviral Immunity and Specific Cytotoxic T Lymphocytes , 1998, The Journal of experimental medicine.

[17]  P. Srivastava,et al.  Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. , 1997, Science.

[18]  P. Srivastava,et al.  Purification of immunogenic heat shock protein 70-peptide complexes by ADP-affinity chromatography. , 1997, Journal of immunological methods.

[19]  P. Srivastava,et al.  A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. , 1995, Science.

[20]  H. Rammensee,et al.  Cross-priming of minor histocompatibility antigen-specific cytotoxic T cells upon immunization with the heat shock protein gp96 , 1995, The Journal of experimental medicine.

[21]  J. Sambrook,et al.  Common and divergent peptide binding specificities of hsp70 molecular chaperones. , 1994, The Journal of biological chemistry.

[22]  K. Sakaguchi,et al.  Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes , 1994, The Journal of experimental medicine.

[23]  G. Parmiani,et al.  Tumor immunity as autoimmunity: tumor antigens include normal self proteins which stimulate anergic peripheral T cells. , 1993, Immunology today.