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Yagawa et al. Cancer immunity and hyperthermia

their therapeutic efficacy is still limited [2,3] . The more includes regional hyperthermia, whole-body hyperthermia,
recent discovery of immune check-point inhibitors and hyperthermic intraperitoneal chemotherapy
has demonstrated sensational long-term benefits in (HIPEC). Ablation therapy, which uses microwave
patients with advanced cancer and has highlighted or a laser at 80-100 °C, leading to direct cancer cell
the importance of immune responses to cancer, but death by heat denaturation of proteins or necrosis [15] ,
its efficacy has been recognized only in a minority of may also be categorized as hyperthermia in the broad
patients [4,5] . Hence, current therapeutic methods need sense. Regional hyperthermia is a less invasive method
to be improved or new therapeutic cancer therapy of thermal therapy. In this method, heat effects are
developed for single or combination use. Recently, limited to the range of irradiation and have an expected
many reports have shown that an appropriate heat role as a chemosensitizer or radiosensitizer used to
effect has potential anticancer efficacy and can augment the efficacy of chemotherapy or radiotherapy
[9]
enhance the efficacy of other cancer therapies. in situ . The currently popular method for hyperthermia
Nonetheless, fever itself is a complex physiological in clinical practice is mild hyperthermia applied to the
response , with the intrinsic effects of elevated body regional cancer area by using an 8 MHz [16,17] or 13.56
[6]
temperature regarded as an important defense system MHz [18] radiofrequency capacitive heating device,
for the body by increasing the immune reaction not applied to the surface of the body directly above the
only against infectious disease but also against cancer. cancer. In contrast, whole body hyperthermia heats
areas of body and increases the systemic body
Hyperthermia temperature of patients [19] . This method is suitable for
Even though the efficacy of intrinsic effects of elevated patients with metastases in multiple organs, including
body temperature in tissues to cells is still being studied, carcinomatosis. Increased effects of immune cells such
it has been disclosed that the survival rate of cells is as T cells and DCs located in the peripheral organs or
reduced by heating at 39-42 °C, and it is amplified circulation are also expected, in addition to the effect of
remarkably by heating at ≥ 42.5 °C for ≥ 1 h. There regional hyperthermia [20] .
is no variation in tolerance between tissue types [7,8] .
Hyperthermia is a type of cancer treatment using this T-cell-based immune responses
feature to target cancer cells and their surrounding to cancer
environment . In the early days, hyperthermia alone T-cells are key immune cells with regard to specific
[9]
at 42-44 °C was performed against recurrent tumors immune responses against cancer. The pivotal events
derived from head and neck cancer and breast cancer, involved in the induction of successful T-cell mediated
immune responses and those in the immune effector
which appeared on the surface of the body. The phase are shown in Figure 1. DCs are the major
objective antitumor response in this set of superficial antigen-presenting cells (APCs), which are capable
tumors was around 40% [10-12] . However, most cancers, of initiating T-cell mediated immune response [21] .
including primary sites as well as recurrent or metastatic These cells usually reside in the epidermis of the skin
sites, are located deep inside the body. This makes and mucosal tissues to prepare to combat foreign
hyperthermia alone less effective because it is quite enemies. This includes cancer antigens, which are
difficult to heat only cancer tissues to more than 42 °C fragments of tumor cells generated as a consequence
using currently available heating devices. Recently, the of natural death or the interaction of tumors and innate
usefulness of mild hyperthermia with 39-42 °C (fever- immune cells such like natural killer (NK) cells [22,23] .
range hyperthermia) for 1-2 h has been reported for DCs process and present these fragments on their cell
combination use with other cancer therapies [13] . This surface along with major histocompatibility complex
method takes advantage of the difference in sensitivity (MHC) antigens after capturing cancer antigens. The
to heat stress between normal tissues and cancerous complex of cancer antigens and MHC class I antigens
tissues. The logic behind its use is that normal are presented to CD8 cytotoxic T lymphocytes (CTLs),
+
tissues have enough vascular distribution to drain the while the complex of cancer antigens and MHC class
congestion of fever and avoid tissue damage in these II antigens engage to stimulate CD4 helper T-cells.
+
shorter time periods. In contrast, in cancerous tissues, The CD4 helper T cells enhance the differentiation of
+
fever and heat stress tend to accumulate. Consequently, CTLs into effecter T-cells by secreting cytokines such
an anticancer effect can be obtained within the fever as interferon-γ (IFN-γ) and interleukin-2 (IL-2).
range while normal tissues endure [14] . Nevertheless,
irradiation for a long period with a higher temperature Naïve T-cells receive the presentation of cancer
than body temperature until cancer is eliminated is still antigens from DCs in the T-cell zones of lymphoid
harmful to normal tissues and homeostasis of the body. organs to acquire an appropriate immune response [24] .
To achieve antigen presentation, these two cells
In widespread use, the term hyperthermia generally constantly migrate to the lymphoid organs (homing).
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017 219