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Yagawa et al. Cancer immunity and hyperthermia

Figure 1: T-cell-mediated immune responses against cancer [76]

The homing mechanism is regulated by chemokines (granzymes) [32,33] . Even though the nature and the role
and the chemokine receptor axis. CCL21 and CCL19 are of these proteases in response to cancer is still unclear,
homeostatic chemokines that are constantly secreted perforins generally act as a carrier for the delivery of
from secondary lymphoid organs, including lymph granzymes and build pores in the plasma membrane of
nodes and Peyer’s patches, without any exogenous target cells to allow granzymes to gain entry to the target
stimulation [25-27] . Meanwhile, C-C chemokine receptor cell cytosol. Granzymes are considered to execute the
7 (CCR7) is a concomitant chemokine receptor of target cells through the cleavage of factors required for
CCL21 and CCL19 [25] . Cells expressing CCR7 can replication and defense [33] . Death ligands are proteins
migrate to organs where CCL21 and CCL19 are including Fas ligand (FasL) that is expressed on
secreted depending on the concentration gradient [28] . effector T-cells. FasL can engage target cells through
Most naïve T-cells constantly express CCR7. DCs the Fas receptor, which belongs to the tumor necrosis
matured by exogenous stimulation with antigens factor (TNF) superfamily, to induce target cell death by
derived from bacteria or cancers begin to express apoptosis [34] . The main role of FasL is to regulate the
CCR7, whereas immature DCs do not express immune system, but cancer cells may over-express
CCR7 [24,29] . Thus naïve T-cells and antigen-presenting FasL spontaneously or as chemotherapy resistance
DCs can migrate to secondary lymphoid organs from to make a countercharge by inducing the apoptosis of
peripheral organs. As a final step in homing, these tumor-infiltrating lymphocytes (TILs) to escape from the
[34]
immune cells need to carry out transvasation through immune system .
high endothelial veins to infiltrate into the lymphatic T-cell based immunotherapy for cancer
organs from the lymphatic system. To complete As has been mentioned, the human immune system
homing through the interval between endothelial cells, always works in response to antigens expressed on
expression of adhesion molecules such as L-selectin cancer cells, thus distinguishing cancer cells from
and integrin is up-regulated for rolling and adhesion noncancerous cells. This causes the induction of
with intercellular adhesion molecule (ICAM), which is a TILs to be found in the tumor microenvironment [35] .
co-receptor for integrin [30,31] . After antigen presentation, However, anticancer immunity is usually not enough
T-cells are induced to proliferate and differentiate into to overcome the tumor’s growing speed owing to the
effecter T-cells. The expression of CCR7 on T-cells is low immunogenicity of cancer cells because these cells
then down-regulated to leave the lymphoid tissue for are derived from an individual’s own cells. Thus, it was
migration to cancer tissues. inevitable that immunotherapy would be developed to
overcome the low immunity against cancer. With regard
Effecter T-cells recognize the complex of cancer to T-cell-based immunotherapy, adoptive transfer of
antigens and MHC class I antigens expressed on CD3-activated T-cells has been induced traditionally
cancer cells through a T-cell receptor (TCR). Then, the as a compulsory activation stimulus to compensate
lethal effects against cancer cells are triggered along for the reduction in stimulation frequency due to low
two different pathways: granule exocytosis and death antigenicity. Moreover cancer-specific-antigen loaded
ligand/death receptor system. Granule exocytosis DC vaccines are also utilized to induce more types of
induces the secretion of perforins and granule enzymes cancer-specific T lymphocytes.

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