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Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT 06030
gp96 is a residential heat shock protein of the endoplasmic
reticulum that has been implicated in the activation of dendritic cells
(DCs) for the initiation of adaptive immunity. By genetic targeting of
gp96 onto the cell surface, we demonstrate that direct access of gp96
to DCs induces their maturation, resulting in secretion of
proinflammatory cytokines IL-1
, IL-12, and chemokine monocyte
chemoattractant protein-1 and up-regulation of the expression of MHC
class I, MHC class II, CD80, CD86, and CD40. Furthermore, surface
expression of gp96 on tumor cells renders them regressive via a T
lymphocyte-dependent mechanism. This work reinforces the notion that
gp96 is an endogenous DC activator and unveils that the context in
which Ag is delivered to the immune system, in this case surface
expression of gp96, has profound influence on immunity. It also
establishes a principle of bridging innate and adaptive immunity for
cancer immunotherapy by surface targeting of an intracellular heat
shock protein.
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