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Yagawa et al. Cancer immunity and hyperthermia

8 A 8 B
# of immunotherapy to elicit skin reaction
7 7

6 6
5 5

4 # of immunotherapy to elicit skin reaction 4
3 3

2 2
1 1

0 0
Immunotherapy Immunotherapy > 38.5 °C for > 38.5 °C for
only + hyperthermia all treatments some treatments
Figure 5: Required number of immunotherapy injections with DC vaccine and activated T-cells to elicit DTH-like skin reaction. (A):
comparison between patients who received immunotherapy alone or in combination use with hyperthermia; (B): comparison of patient’s
[76]
rectal temperatures during hyperthermia . DC: dendritic cell; DTH: delayed type hypersensitivity

MICA and increased cytotoxicity of NK cells were also renal, and pancreatic cancer [70] . Depletion of Tregs in
observed in several cancer cell lines [66] . Concerning animal models has been shown to increase the efficacy
the contribution of NK cells to cancer-specific immune of immunotherapy. So, achieving the depletion of
responses, after an initial attack, fragments including Tregs is one of the pivotal targets of recent research
cancer antigens of tumor cells are generated as a result and therapy associated with cancer immunology [71] .
of the interaction of the tumor and NK cells. These The potential effect of hyperthermia is considered to
cancer antigens are recognized by DCs for T-cell- enhance the cytotoxicity of NK cells against Tregs, and
based cancer-specific immune responses. Additionally, to inhibit the induction of Tregs while the apoptosis of
activated NK cells secrete cytokines including IFN-γ Tregs is induced. A significant decrease in the number
and IL-2 to enhance acquired immune responses with of Tregs was observed while NK cell activity and the
immunoglobulin production from B-cells and activation percentage of NK cells increased in peripheral blood
of T-cells [55,61] . This perception leads to the conclusion samples of healthy volunteers after irradiation of fever-
that increasing the function of NK cells by hyperthermia range hyperthermia to the upper abdominal region [72] .
could be expected to result in the augmentation not only Moreover, combination therapy of intratumoral injection
of nonspecific anticancer immune reactions regulated of immature DCs and local hyperthermia for patients
by NK cells but also of specific anticancer immune with advanced malignant melanoma demonstrated
reactions regulated by T-cells and DCs. decreased infiltration of Tregs and increased infiltration
of activated CTLs, even though there was no statistical
To avoid exaggerated immune responses that cause difference in overall survival time [73] .
harmful effects on the body, the immune system is
regulated to limit adaptive immune responses and The efficacy of hyperthermia in down-regulating the
prevent autoimmune responses and auto-inflammatory expression of PD-L1 in some cancer cell lines was
reactivity in the normal situations. To achieve this, our reported. In this study, decreased expression of PD-
immune system combines immunological tolerance L1 in cancer cell lines was shown when samples were
system. Regulatory T cells (Tregs) are a subpopulation exposed to temperatures between 40 °C and 43 °C [74] .
of T-cells, expressing CD4, CD25, and FOXP3, which Further accumulation of data associated with this new
negatively modulate both innate and adopted immune experimental model is eagerly awaited.
response by down-regulating or suppressing induction
and proliferation of immune cells including T cells, DCs, Combination therapy with immunotherapy
and NK cells [67-69] . Even though Tregs usually account Hyperthermia has been reported to enhance the efficacy
for about 4% of CD4 T cells, they can make up as of DC vaccines by up-regulating IFN-γ secretion to
+
much as 20-30% of the total CD4 population in the stimulate naïve T-cells, enhancing DC migration toward
+
tumor microenvironment and are associated with poor lymphatic organs and protecting DC from apoptosis [75] .
prognosis in many cancers, such as ovarian, breast, We introduced a whole body hyperthermia device

224 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017