Biomedical Engineering Reference
In-Depth Information
Kupffer cell activity may be one of the major factors involved
in the progressive injury after thermal ablation [34]. Heat induces
Kupffer cells to secrete IL-1 [45] and tumor necrosis factor-α
(TNF-α) [46], which are known to have
in vivo
antitumor activity
[47] and to increase apoptosis in cancer cells [44]. Kupffer cells
also induce the production of interferon that augments the liver-
associated natural killer cell activity [48].
Thermal ablation may induce both regional and systemic pro-
duction of cytokines through activation of inflammatory cells.
Compared with controls, the circulating level of IFN-γ and vascu-
lar endothelial growth factor levels markedly increase after RFA
[49,50]. The increased levels of IL-1 and TNF-α are also observed
after RFA [51]. These cytokines may have direct cytotoxic effects
such as inducing tumor endothelial injury and tumor cells more
sensitive to heat-induced damage [52,53]. However, contrasting
results were obtained for TNF-α level in two studies [50,54] and
IL-1 level in one study [55], which remains unchanged after ther-
mal ablation.
an effective vaccine to elicit tumor-specific immune responses,
including induction of CTL cytotoxic activity and protection
against a lethal tumor challenge in naïve mice. When the tumor
debris was loaded with immature DCs, it could significantly
induce maturation of DCs, and increased cytotoxocity and
TNF-α and IFN-γ secretion by CTL, thus initiating host-specific
immune response after H22 challenge in the vaccinated mice
[63]. Immediately after HIFU exposure to MC-38 colon adeno-
carcinoma cells
in vitro
, the release of endogenous danger signals
including HSP60 was observed from the damaged cells. These
signals could subsequently activate antigen presenting cells
(APCs), leading to an increased expression of co-stimulatory
molecules and enhanced secretion of IL-12 by the DCs, and ele-
vated secretion of TNF-α by the macrophages [64]. In addition,
HIFU could upregulate
in vitro
and
ex vitro
molecule expression
of HSP70 [65,66], which are intracellular molecular chaperones
that can enhance tumor cell immunogenicity, resulting in potent
cellular immune responses.
The potency of APCs activation from mechanical lysis and a
sparse-scan HIFU was much stronger than that from thermal
necrosis and a dense-scan HIFU exposure, suggesting that opti-
mization of HIFU ablation strategy may help to enhance immune
response after treatment [67, 68]. Heat and acoustic cavitation are
two major mechanisms involved in HIFU-induced tissue dam-
age, and cavitation is a unique effect of HIFU when compared
with other thermal ablation techniques. It causes membranous
organelles to collapse, including mitochondria and endoplasmic
reticulum, cell, and nuclear membrane. This breaks up tumor
cells into small pieces, on which the tumor antigens may remain
intact, or lead to the exposure of an immunogenic moiety that
is normally hidden in tumor antigens [56]. Zhou and colleagues
[68] used either heat- or HIFU-treated H22 tumor vaccine to
inoculate naïve mice. The vaccination times were four sessions,
once a week for four consecutive weeks, and each mouse was
challenged with H22 tumor cells one week after the last vaccina-
tion. They found that the HIFU-treated tumor vaccine could sig-
nificantly inhibit tumor growth and increase survival rates in the
vaccinated mice, suggesting that acoustic cavitation could play
an important role to stimulate host antitumor immune system.
Emerging clinical results revealed that systemic cellular
immune response was observed in cancer patients after HIFU
treatment. Rosberger and colleagues [69] reported five consecu-
tive cases of posterior choroidal melanoma treated with HIFU.
Three patients had abnormal, and two patients normal, CD4/CD8
ratios before treatment. One week after treatment, the ratio in
two patients reverted to normal, while another was noted to have
a 37% increase in his CD4T-cells relative to his CD8 cells. Wang
and Sun [70] used multiple-session HIFU to treat 15 patients
with late-stage pancreatic cancer. Although there was an increase
in the average values of NK cell and T lymphocyte and subset in
10 patients after HIFU treatment, a significant statistical differ-
ence was observed in only NK cell activity before and after HIFU
treatment (p < 0.05). Wu and colleagues [71] observed changes
in circulating NK, T lymphocyte, and subsets in 16 patients with
solid malignancy before and after HIFU treatment. The results
15.3.4 antitumor Immune response
after HIFU treatment
It has been noted that large amounts of tumor debris remain
in situ
after thermal ablation. As a normal process of healing
response, the tumor debris is gradually reabsorbed by the indi-
vidual patient, which takes a period ranging from months to few
years. It is still unclear what kind of biological significance may
exist during the absorption of the ablated tumor. However, some
studies have shown that active immune response to the treated
tumor could be developed after thermal ablation, and the host
immune system could become more sensitive to the tumor cells
[56-59]. This may lead to a potential procedure that reduces or
perhaps eliminates metastases, and prevents local recurrence in
cancer patients who have had original dysfunction of antitumor
immunity before treatment.
Animal studies have suggested that HIFU may modulate host
antitumor immunity. Yang and colleagues [60] used HIFU to
treat C1300 neuroblastoma implanted in mouse flanks, followed
by the rechallenge of the same tumor cells. A significantly slower
growth of reimplanted tumors was observed in these mice while
compared with the controls. After HIFU treatment, the cyto-
toxicity of peripheral blood T-lymphocytes was significantly
increased in the H22 tumor-bearing mice treated with HIFU,
and adoptive transfer of the activated lymphocytes could pro-
vide better long-term survival and lower metastatic rates in the
mice rechallenged by the same tumor cells [56]. Similar results
were confirmed in the mice implanted with MC-38 colon ade-
nocarcinoma after HIFU ablation. HIFU treatment could also
induce an enhanced CTLs activity
in vivo
, and thus provided
protection against subsequent tumor rechallenge [61].
After HIFU ablation, large amounts of tumor debris remain
in
situ
, and the host gradually reabsorbs them as the normal process
of a healing response. Using a murine hepatocelluar carcinoma
model, Zhang and colleagues [62] demonstrated that the remain-
ing tumor debris induced by HIFU could be immunogenic as
