My laboratory has previously found that the immunogenicity of tumor cells cosegregates with the expression of the inducible hsp70 but not with the constitutive hsc70. Various clones derived from the same primary tumor were either spontaneously rejected by the alphabeta-TCR positive cell component of the immune system or grew progressively and killed the host. Surprisingly, classical immunological markers like MHC-I, MHC-II, I-CAM and others where not associated with this difference of behavior in vivo. We observed that clones having the ability to synthesize the strictly inducible hsp70 were rejected by the immune system. Conversely, the clones that grew progressively do not synthesize the inducible hsp70 synthesis. This cosegregation was confirmed by the selection of multiple variants, independently of the expression of the constitutive hsc70 and of other immunological markers. We propose to : (i) Purify the inducible hsp70 and the constitutive hsc70 from tumor cells and determine their respective immunogenicity. (ii) Genetically manipulate the hsp70 and hsc70 specific domains in order to study their requirements for their unique immunological properties. (iii) Analyze the peptides associated with inducible hsp70 and constitutive hsc70. The study of the strictly inducible hsp70 participates in both the fundamental understanding of the immune system and the new generation of HSP-based anti-cancer vaccines. The HSP70-derived tumors have been used successfully against murine cancers and are currently under investigation in humans. The possibility that the inducible HSPs have a superior immunogenicity than the constitutively expressed HSPs has not been explored so far and might be of considerable benefit for public health.
| Menoret, Antoine (2004) Purification of recombinant and endogenous HSP70s. Methods 32:7-12 |
| Callahan, Margaret K; Chaillot, Delphine; Jacquin, Claire et al. (2002) Differential acquisition of antigenic peptides by Hsp70 and Hsc70 under oxidative conditions. J Biol Chem 277:33604-9 |
| Li, Zihai; Menoret, Antoine; Srivastava, Pramod (2002) Roles of heat-shock proteins in antigen presentation and cross-presentation. Curr Opin Immunol 14:45-51 |
| Menoret, A; Chaillot, D; Callahan, M et al. (2002) Hsp70, an immunological actor playing with the intracellular self under oxidative stress. Int J Hyperthermia 18:490-505 |
| Clark, P R; Menoret, A (2001) The inducible Hsp70 as a marker of tumor immunogenicity. Cell Stress Chaperones 6:121-5 |
