The Journal of Experimental Medicine
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Published 2 December 2002. doi:10.1084/jem.20020436
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© Rockefeller University Press, 0022-1007/2002/12/1447/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 11, December 2, 2002 1447-1459
GRP94 (gp96) and GRP94 N-Terminal Geldanamycin Binding Domain Elicit Tissue Nonrestricted Tumor Suppression

Julie C. Baker-LePain1, Marcella Sarzotti2, Timothy A. Fields3, Chuan-Yuan Li4 and Christopher V. Nicchitta1

1 Department of Cell Biology, Duke University Medical Center, Durham, NC 27710
2 Department of Immunology, Duke University Medical Center, Durham, NC 27710
3 Department of Pathology, Duke University Medical Center, Durham, NC 27710
4 Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710

Address correspondence to Christopher V. Nicchitta, Department of Cell Biology, Duke University Medical Center, 366 Nanaline H. Duke, Durham, NC 27710. Phone: 919-684-8948; Fax: 919-684-5481; E-mail: c.nicchitta{at}cellbio.duke.edu

In chemical carcinogenesis models, GRP94 (gp96) elicits tumor-specific protective immunity. The tumor specificity of this response is thought to reflect immune responses to GRP94-bound peptide antigens, the cohort of which uniquely identifies the GRP94 tissue of origin. In this study, we examined the apparent tissue restriction of GRP94-elicited protective immunity in a 4T1 mammary carcinoma model. We report that the vaccination of BALB/c mice with irradiated fibroblasts expressing a secretory form of GRP94 markedly suppressed 4T1 tumor growth and metastasis. In addition, vaccination with irradiated cells secreting the GRP94 NH2-terminal geldanamycin-binding domain (NTD), a region lacking canonical peptide-binding motifs, yielded a similar suppression of tumor growth and metastatic progression. Conditioned media from cultures of GRP94 or GRP94 NTD-secreting fibroblasts elicited the up-regulation of major histocompatibility complex class II and CD86 in dendritic cell cultures, consistent with a natural adjuvant function for GRP94 and the GRP94 NTD. Based on these findings, we propose that GRP94-elicited tumor suppression can occur independent of the GRP94 tissue of origin and suggest a primary role for GRP4 natural adjuvant function in antitumor immune responses.

Key Words: chaperone • heat shock protein • dendritic cell • cancer • immunotherapy


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