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Oiseth et al. Cancer immunotherapy

classically considered to be comprised of the innate these evasive mechanisms represent the major
and adaptive arms, although this is a simplification area of interest in current CI research. The concept
since these arms have overlapping functions and are that the immune system is capable of detecting and
intimately related. The innate immune system includes killing nascent “non-self” malignant cells was first
dendritic cells, natural killer cells (NK), macrophages, developed by Burnet [30,31] and Thomas [32] in their cancer
neutrophils, eosinophils, basophils, and mast cells. immunosurveillance hypothesis. The concept was not
Innate immune cells do not require prior stimulation accepted initially but it is now considered a component
by antigens and act as a first line of defense against of cancer immunoediting, whereby the surveillance
foreign antigens. The adaptive immune system includes system can determine or “shape” the immunogenicity of
B lymphocytes, CD4 helper T lymphocytes, and CD8 the tumor cells which are not eliminated initially [33] . The
+
+
cytotoxic T lymphocytes (CTLs), and requires formal immunoediting process has been formally divided into
presentation by antigen-presenting cells (APCs) for its three main phases: elimination, equilibrium, and escape.
activation [21] . The adaptive immune system generates The elimination phase refers to the initial damage and
antigen-specific T- and B-cell lymphocytes. The immune possible destruction of tumor cells by the innate immune
system is highly variable between individuals but system, followed by presentation of the tumor antigens
relatively stable over time within a given person [22] . in the cellular debris to dendritic cells which then present
them to T-cells and thereby create tumor-specific CD4
+
+
Each cell is estimated to experience over 20,000 DNA and CD8 T-cells. These help destroy the remaining
damaging events each day [23] , which are normally tumor cells if elimination is complete. The equilibrium
repaired by specific DNA repair pathways with no phase occurs when any tumor cells survive the initial
lasting effects [24] . Cells which are not repaired and elimination attempt but are not able to progress, being
which acquire malignant or potentially malignant maintained in a state of equilibrium with the immune
changes are then usually recognized and killed by cells. In the escape phase, cancer cells grow and
the tumor immunosurveillance system. This involves metastasize due to loss of control by the immune
system. The cancer cells which are not eliminated
predominantly cell-mediated mechanisms that can and which escape may do this by expressing fewer
differentiate between self and non-self antigens. Since antigens on their surfaces or even by losing their MHC
a malignant cell can have more than 11,000 genomic class I expression [34] . They may also show the ability
mutations, many new tumor-associated antigens to protect themselves from T-cell attack by expressing
(TAAs) may be expressed [25] . TAAs include products immune checkpoint (IC) molecules on their surfaces
of mutated proto-oncogenes, tumor suppressor genes, like normal cells; these IC molecules are upregulated
overexpressed or aberrantly expressed proteins, tumor by cytokines produced by activated T-cells and are part
antigens produced by oncogenic viruses, oncofetal of a normal negative feedback loop to control excessive
antigens, altered glycolipids and glycoproteins, and tissue damage from inflammation by downregulating or
cell type-specific differentiation antigens. These new suppressing T-cells [35] .
TAAs, or fragments thereof, are presented on the cell
surfaces with their major histocompatibility complex The dynamic that exists between the immune system
(MHC) molecules. However, recognition of an antigen- and tumor antigens is a phenomenon recognized
MHC complex by a T-cell antigen receptor is insufficient relatively recently, since it was only in 1991 that van der
for the initial activation of naive T-cells, requiring Bruggen and colleagues first reported the existence of
additional costimulatory signals that are provided by the a human tumor antigen recognized by T-cells [36] . They
engagement of the CD28 receptor on the T-cell surface were able to clone the melanoma antigen-encoding
with B7 ligand molecules (two of which are CD80 and gene (MAGE), which encodes an antigen recognized
CD86) on the APCs. This CD28 receptor/B7 ligand by cytotoxic T-cells. This provided not only proof that the
combination or “immunological synapse” stimulates immune system was capable of seeking and destroying
the proliferation and function of the T-cells. Many other tumor cells but also provided the first identification of a
receptor/ligand combinations are possible between molecular target.
activated T-cells and other cells, including tumor cells,
and some of these interactions are inhibitory, such as The ability of cancer cells to evade immune destruction
PD-1/PD-L1 and CTLA-4/B7 [26-29] , and are discussed has been proposed as the eighth hallmark of cancer [37] .
later in this monograph. As noted above, a tumor is able to do this not only by
modulating its own cellular characteristics but also by
Some malignant cells are able to evade the tumor creating its own “tumor microenvironment” by recruiting
immunosurveillance system by manipulating their apparently normal immune cells to help shield it from
own characteristics as well as the cells in their attack by the immune system. Through the production
microenvironment to become “successful” tumors; of various cytokines and chemokines, successful
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