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.
Castelli
C
C
Unit of Immunotherapy of Human Tumors, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Ciupitu
A M
AM
Rini
F
F
Rivoltini
L
L
Mazzocchi
A
A
Kiessling
R
R
Parmiani
G
G
D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008545:Melanoma / Q000737:chemistry / Q000276:immunology*; D018832:Molecular Chaperones / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D018840:HSP70 Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D018832:Molecular Chaperones