Impact of Heat Shock Proteins and Stress on the immune response, application to vaccine design
Quae medicamenta non sanat, ferrum sanat. Quae ferum non sanat, ignis sanat. Quae vero ignis non sanat, insanabilia reportari oportet.
(That which drugs fail to cure, the scalpel can cure. That which the scalpel fails to cure, heat can cure. If the heat cannot cure, it must be determined to be incurable.) -Hippocrates.
Cells subject to stresses, such as an increase of temperature, have a decrease in normal protein synthesis and induction of a set of several specific protein chaperones called Heat Shock Proteins (HSPs). HSPs are not only induced by heat but also by stresses concomitant to the development of an immune response such as fever, infection, cytokine stimulation, metabolic starvation and cell death. The adaptive value of this "heat shock" response contributes to an increased resistance to stress at a cellular level and possibly at a systemic level through the action of the immune system. The mechanism by which HSPs are integrated in the immune response has been related to their ability to chaperone immunogenic peptides and to specifically immunize against tumor and virus-infected cells.
Our working hypothesis is that physiological induction of a specific set of HSPs, increases cell immunogenicity and in consequence enhances the ability of the immune system to discriminate between self and non-self entities. In this context our laboratory has previously found that the immunogenicity of tumor cells cosegregates with the expression of the inducible chaperone Hsp70 but not with other constitutively expressed chaperones such as Hsc 70. Various clones derived from the same primary tumor were either spontaneously rejected by the ab-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 were not associated with this difference of behavior in vivo. We observed that clones that have the ability to synthesize the inducible Hsp70 were rejected by the immune system. Conversely, the clones that grew progressively did not synthesize the inducible Hsp70. This cosegregation was confirmed by the selection of multiple variants, independently of the expression of the constitutive Hsc 70 and of other immunological markers. Increase of immunogenicity of tumor cells transfected with the inducible hsp70.1 gene has confirmed the immunological importance of Hsp70.
The general objective of this laboratory is to understand the immunological role of stress and inducible HSPs and to apply this to treatment of cancer and infectious diseases. We are currently analyzing the respective immunogenicity of Hsp70 and Hsc70, the immunological consequences of their expression, their role in immune surveillance, and the mechanisms by which stress, fever, the inducible Hsp70 and other inducible molecules mediate immunogenicity. These studies contribute to both the fundamental understanding of the immune system and the new generation of HSP-based anti-cancer vaccines. HSP-derived tumors have been used successfully against animal cancers and are currently under investigation in humans in association with our laboratory.
Selected Publications
- Li Z., Ménoret A., Srivastava P.K., Roles of heat shock proteins in antigen presentation and cross-presentation. Current Opinion Immunology, 14: 45-51 (2002).
- Ménoret A, Niswonger M.L., Altmeyer A, Srivastava P.K. A peptide-binding, MHC class I-binding chaperone of the lumen of the endoplasmic reticulum is an aminopeptidase. J. Biol. Chem. 276: 33313-33318 (2001).
- Clark P, Ménoret A. The inducible hsp70 as a marker of tumor immunogenicity. Cell Stress Chaperone. 6: 121-125 (2001).
- Robert J. *, Ménoret A.*, Basu S, Cohen N, Srivastava P.K. Phylogenic conservation of the molecular and immunological properties of the chaperones gp96 and hsp70. Eur. J. Immunol. 31: 186-195 (2001).
* co-first authors.
- Ménoret A, Chandawarkar RY, Srivastava PK. Natural autoantibodies against heat shock proteins hsp70 and gp96: implications for immunotherapy using heat shock proteins..Immunology.101:.364-370 (2000).
- Ménoret A. Immunological significance of hsp70 in tumor rejection. Immunology in Medicine Series. Nottingham, Rees R. C. (ed) 157-169 (2000).
- Ménoret A., Bell G. Purification of multiple heat shock proteins from a single tumor sample. J. Immunol. Meth. 237: 119-130 (2000).
- Ménoret A, Peng P, Srivastava PK. Association of peptides with the endoplasmic reticular heat shock protein gp96 occurs in vivo and is not a post cell lysis event. Bioch. Biophys. Res. Co. 262: 813-818 (1999).
- Ménoret A,. Chandawarkar R.Y. Heat shock protein-based anticancer immunotherapy, an idea whose time has come Seminar in Oncology 25 (6): 654-660 (1998).
- Srivastava P.K., Ménoret A., Basu S., Binder R., McQuade K.L. Heat shock proteins come of age: primitive function acquire new roles in an adaptive world. Immunity 8, 657-665 (1998).
- Ménoret A, Srivastava PK. The cancer micro-environment and its impact on immune response to cancer. Molecular approaches to tumor immunotherapy, Chapter 5: 108-120. New-York, Liu Y (ed) (1998).
- Peng P, Ménoret A, Srivastava PK. Purification of immunogenic heat shock protein 70-peptide complexes by ADP-affinity chromatography. J. Immunol. Meth. 204: 13-21 (1997).
- Ménoret A, Party Y, Burg C, and Le Pendu J. Co-segregation of tumor immunogenicity with expression of inducible but not constitutive hsp70 in rat colon carcinomas. J Immunology 155, 740-747 (1995).
- Ménoret, A. 1994. Influence of protectors to metabolic stress on the immunogenicity of tumorous cells. Ph. D. Thesis., FRANCE (1994).
- Ménoret A, Labarriere NE, Breimer ME, Piller F, Le Pendu J. Involvement of carbohydrate blood group antigens in the phenomenon of cellular heat resistance. Glycoconjugate Journal 10, 4, 307 (1993).
PDF files of these publications are available upon request to menoret@up.uchc.edu
Key words: HSP, heat, stress, immunity, cancer, antigens, therapy, Hsp70, Hsc70, antigen.
