Vaccination with tumor-derived GRP94/gp96, the endoplasmic reticulum Hsp90 molecular chaperone, can elicit suppression of tumor growth and metastasis. The substantial therapeutic efficacy of GRP94/gp96 in prophylactic and therapeutic vaccination of mice has prompted its clinical evaluation as an immunotherapeutic for treatment of cancer in humans. Currently, GRP94/gp96 is undergoing Phase III trials for kidney cancer and melanoma. Although GRP94/gp96 has generated substantial interest as a novel immunotherapeutic, its mechanism of action remains unknown. The broad, long-term objective of the proposed research is to identify the mechanism of GRP94/gp96-mediated anti-tumor immune responses. This objective will be accomplished in the following specific aims: 1. Define the immunological basis for a gp96-secreting, cell-based tumor vaccine strategy; 2. Determine the role of gp96 and gp96 NTD in the regulation of innate immune responses. 3. Examine the role of gp96 and gp96 NTD in early immune modulation of retrovirus-induced disease. 4. Identify the effector cells and effector cell receptor(s) functioning in gp96/gp96NTD recognition and cell activation. The proposed studies will utilize a recently developed novel immunization strategy wherein animals are vaccinated with cells expressing a secretory form of GRP94/gp96. Using this experimental approach, we have demonstrated that GRP94/gp96-mediated tumor rejection is independent of the tissue of origin and thusGRP94/gp96-elicited anti-tumor immune responses can be elicited using GRP94/gp96 of non-tumor origin. Given the absence of tumor-restriction identified in these experiments, we hypothesize that GRP94/gp96functions through activation of innate immune responses. Such responses are a necessary prerequisite to robust anti-cancer adaptive immune responses. In executing the Specific Aims presented above, we will define the efficacy of the gp96-secreting, cell-based tumor vaccine strategy in multiple tumor models, using prophylactic and therapeutic immunization strategies. Detailed studies of the interactions of GRP94/gp96 with effector cells of the innate immune system will be performed. These studies will emphasize in vivo models and analyses of in vivo cellular responses. To better define the mechanism of GRP94/gp96 interaction with the innate immune system, we propose to extend analyses to the study of retrovirus-induced disease, in a neonate model, and to identification of signaling pathways accessed by GRP94/gp96.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104392-03
Application #
7026918
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Yovandich, Jason L
Project Start
2004-04-01
Project End
2009-02-28
Budget Start
2006-04-01
Budget End
2007-02-28
Support Year
3
Fiscal Year
2006
Total Cost
$246,625
Indirect Cost
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Jockheck-Clark, Angela R; Bowers, Edith V; Totonchy, Mariam B et al. (2010) Re-examination of CD91 function in GRP94 (glycoprotein 96) surface binding, uptake, and peptide cross-presentation. J Immunol 185:6819-30
Maynard, Jason C; Pham, Trang; Zheng, Tianli et al. (2010) Gp93, the Drosophila GRP94 ortholog, is required for gut epithelial homeostasis and nutrient assimilation-coupled growth control. Dev Biol 339:295-306
Huang, Qi-Quan; Sobkoviak, Rudina; Jockheck-Clark, Angela R et al. (2009) Heat shock protein 96 is elevated in rheumatoid arthritis and activates macrophages primarily via TLR2 signaling. J Immunol 182:4965-73
Lev, Avital; Dimberu, Peniel; Das, Suman R et al. (2009) Efficient cross-priming of antiviral CD8+ T cells by antigen donor cells is GRP94 independent. J Immunol 183:4205-10