Potentiating Immune System by Hyperthermia
Hyperthermia enhances the host immune responses against cancer through several mechanisms; activating immune cells (e.g., natural killer cells, dendritic cells, and cytotoxic T lymphocytes), canceling immune suppression, altering cell-surface molecules on cancer cells, and modifying adhesion molecules on immune cells and endothelial cells. This chapter discusses the positive effects of hyperthermia on the host immune system.
KeywordsHyperthermia Fever-range hyperthermia Mild hyperthermia NK cell Dendritic cell Cytotoxic T cell Regulatory T cell
The immune system distinguishes between self and non-self to identify and remove foreign substances, including cancer cells. Innate immunity, unlike acquired immunity, can immediately respond to foreign substances without prior exposure to antigens. Natural killer (NK) cells are at the front line of innate immune response in attacking cancer cells. Dendritic cells (DCs) capture, process, and display cancer antigens in order to transmit activation signals to the antigen-specific acquired immune response, which cytotoxic T lymphocytes (CTLs) are major players in. Regulatory T cells (Treg) counteract the anti-cancer immune responses described above.
Hyperthermia treatment raises the temperature of target tissues to 42.5 °C or above when destroying cancer cells, and to 38–41 °C (fever-range hyperthermia or mild hyperthermia) when increasing blood flow and activating immune reactions. When a cancer mass is heated over 42.5 °C, both cancer and immune cells in the center part of the lesion are destroyed, whereas the surrounding areas form a thermal gradient to generate a field of 38–41 °C, where immune reactions are activated as fever-range hyperthermia.
The effects of fever-range hyperthermia on immune cells and their networks are discussed in this chapter.
12.2 Enhancing Anti-Cancer Activity of NK Cells Using Hyperthermia
Frequencies of reduced MHC class I expression in surgically removed tumors
Low or negative cases/total cases
Grade 2 astrocytoma
Head & neck cancer
Renal cell cancer
Bone and soft tissue sarcoma
Activated NK cells directly attack cancer cells using cytotoxic molecules (e.g., perforin and granzyme), death receptors (e.g., FasL, TRAIL, TNF-α), and antibody-dependent cell-mediated cytotoxicity (ADCC) [1, 2]. They also secrete cytokines such as IFN-γ, TNF-α, GM-CSF and IL-2 to stimulate other immune cells (i.e., DC, T and B lymphocytes), which reinforce acquired immunity by enhancing antigen-specific CTL induction and immunoglobulin production [1, 2].
Hyperthermia also increases the MICA mRNA levels in tumors, which correlate with increased sensitivity to cytolysis . The interaction between NKG2D and MICA/B is just an example, and interactions between other NK cell-activating or inhibitory receptors and ligands are also important in enhancing the cytotoxicity of NK cells against cancer cells . Hyperthermia enhances the anti-cancer activity of NK cells through these molecular events.
12.3 Activating DC and CTL by Hyperthermia
DCs are key players in antigen-specific CTL induction for acquired immunity against cancer cells. DCs capture and process cancer antigens originating from damaged cancer cells before presenting them on the cell surface along with MHC antigens. The complex made up of cancer antigens and MHC class II antigens stimulates helper T cells, while the complex made up of cancer antigens and MHC class I antigens induces CTLs via cross-presentation. The resulting CTLs recognize cancer cells through the cancer antigen presented on the MHC class I antigen, and thus attacks them.
Hyperthermia causes the generation of heat shock proteins (HSPs), which serve as molecular chaperones, in cancer cells. HSPs enhance the intracellular transport of cancer antigens generated in proteasomes and are presented on the cell surface along with the MHC class I antigen to induce antigen-specific CTLs [6, 7, 8].
The complex of HSPs and cancer antigens can also be released to the extracellular space when cancer cells are destroyed. Such complexes are captured by DCs, which express HSP receptors, and are processed for cross-presentation to efficiently induce antigen-specific CTLs .
DCs and CTLs are activated further by cytokines released from T lymphocytes, which are also activated by hyperthermia .
In order to make T cells interact with DCs for CTL induction in lymphoid organs, it is crucial to recruit T cells into lymphoid organs. Thermal stress up-regulates the expression of adhesion molecules such as L-selectin and α4β7 integrin on lymphocytes, and CCL21+ and ICAM-1 on high endothelial venules, which serve as gatekeepers for lymphocyte recruitment into lymphoid organs . Interestingly, CD3-negative CD56-bright NK cells also highly express L-selectin, and these immunomodulatory NK cells may activate DCs to induce CTLs.
12.4 Release from Immune Suppression and Hyperthermia
The balance between immunity and tolerance has to be coordinated in a finely tuned manner within the body. Tolerance is critically important in protecting oneself from autoimmune response. Cancer cells, however, take advantage of the tolerance mechanisms to escape immune surveillance; e.g., by utilizing Tregs, which negatively regulate both innate and acquired immunity at least in vitro by suppressing the function of immune cells including T lymphocytes, B lymphocytes, DCs, and NK cells [14, 15].
The number of Tregs within the peripheral blood as well as in cancer tissues is higher in cancer patients compared to that of non-cancer individuals. Moreover, cancer patients with increased numbers of Tregs in cancer tissues have poorer prognoses (cervical, renal, hepatocellular, gastric, and breast cancers and malignant melanoma) and higher risks of recurrence (lung, gastric, and hepatocellular carcinomas and malignant melanoma) . These observations imply that cancer patients are prone to cancer growth due to the immune suppression caused by Tregs.
Malignant melanoma patients who were treated with a combination of hyperthermia and intratumoral injection of immature DCs exhibited lower numbers of Tregs and higher numbers of CTLs compared to patients treated without hyperthermia . Furthermore, patients with hyperthermia showed significant delays in cancer growth. These results suggest that hyperthermia exerts therapeutic benefits at least partly by decreasing the number of Tregs in cancer tissues. We also observed a decrease in the number of Tregs within the peripheral blood after applying fever-range hyperthermia to the upper abdomen of healthy individuals . Hyperthermia could be reducing the number of Tregs by inducing the apoptosis of Tregs, enhancing NK cytotoxicity against Tregs, or inhibiting the induction of Tregs. Further studies are needed to clarify the precise mechanisms of the hyperthermia-induced decrease of Tregs.
Better uses of hyperthermia will be achieved by further understanding of its effects on the immune system. Additionally, clinical data on cancer treatments using hyperthermia in combination with other therapies need to be accumulated and evaluated for their respective clinical efficacies. These efforts will lead to the development of efficient combinatory therapies using immune therapy, chemotherapy, radiation, and hyperthermia.
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