Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

12.2 Cancer Immunotherapy Strategies with HSPs
Most HSPs are constitutively expressed, although under stress conditions their expression
can be up-regulated to different degrees. For example, the inducible HSP70
in the cytosol seems to be strictly regulated by stress and not expressed at the basal
level, whereas the endoplasmic reticulum (ER) homolog of HSP70, grp78 or Bip, is
expressed at high levels under non-stress conditions. Moreover, there seem to be ªno
rulesº governing the subcellular localization of HSPs. ER HSPs including gp96 can
be displayed on the cell surface during stress and under certain physiological conditions
[67±70]. Mechanistic studies of gp96 in cross-presentation of antigens suggested
that extracellular gp96 gains access to the cytosolic compartment [37, 43, 44,
71]. Moreover, secretion, surface expression and transport across the plasma membrane
of a cytosolic HSP70 have been demonstrated [47, 72, 73]. Surface HSP70 can
also serve as a direct target for the immune system [47]. Recently, it has been suggested
that the surface forms of supposedly cytosolic HSP70 and HSP90 might participate
in the receptor clustering for CD14-independent lipopolysaccharide (LPS) signaling
[74].
Due to the emerging knowledge about HSPs in the immune response, whole cells
engineered to express HSPs at different levels and different sites have now been
tested for immunotherapy of cancer. Such effort has also challenged cell biologists
for the basis of plasticity of subcellular transport of HSPs, and immunologists for
the significance of ªectopicº expression of HSPs in immunoregulation in both physiological
and pathophysiological conditions.
12.2.3.1 Modulation of the level of HSPs for cancer immunotherapy
The attempt to modulate the expression of HSPs, knowingly or unknowingly, has
been an ancient practice. Induction of local heat by way of moxibustion by the Chinese
for the treatment of infections or other diseases is as old as human civilization.
Systemic heat can also be induced by herbs and other natural substances to change
the balance of ªYingº and ªYangº for man's health and longevity. Despite this long
practice and phenomenology, the experience and mechanism of thermotherapy as
an established modality for treatment of cancers is still very limited [75].
Repasky's group has begun, systemically, the examination of the role and mechanism
of fever in modulating immune responses and anti-tumor effects by a mild fever-range
hyperthermia protocol. They found that hyperthermia (i) increases the
homing of lymphocytes (Langerhans cells) to the draining lymph nodes, resulting in
increased contact hypersensitivity [76] and decreases the number of lymphocytes in
the circulation, peritoneal cavity and spleen [77]; (ii) potentiates LPS-induced interleukin
(IL)-6 and tumor necrosis factor (TNF)-a production [78]; (iii) induces a reorganization
of protein kinase C, spectrin and HSP70 into a large cytoplasmic aggregate
[79]; and (iv) causes increased tumor infiltration and function of NK cells [80].
The effect of heat shock on tumor immunogenicity has been investigated. Heat treatment
of colon-26 cells induced HSP70, but not other HSPs. Immunization of
BALB/cJ mice with heat-treated colon-26 cell extract, which was enriched in HSP70,
elicited anti-tumor immunity against s.c. injected colon-26 cells [81]. Furthermore,
combination therapy of heat treatment and immunization with heat-treated colon-26
cell extract significantly reduced tumor volumes compared with heat treatment
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