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often seen in tumor cells to avoid recognition. Defects at different layers of the MHC class I
ROLE FOR THE IMMUNE SYSTEM IN CANCER
processing machinery are found. For example, mutations or loss of LMP-2 and -7, subunits
In 1891 Dr William Coley, often referred to as the “Father of Immunotherapy”, was the first
of the multicatalytic proteasome complex generating peptide fragments, TAP1 and TAP2
transporting these peptides into the endoplasmic reticulum (ER) , β2-microglobulin (β2m)
21
22
to search for a method to activate the immune system as an alternative treatment method
stabilizing the MHC heavy chain were described. Although reduced MHC expression results
for sarcoma, after witnessing the painful death of an 18-year-old patient. For this, he used
in reduced susceptibility to cytotoxic T cells, the vulnerability to NK cell lysis increases, as
a mixture of live and inactivated Streptococcus pyogenes and Serratia marcescens , leading
7,8
NK cells rely on a balance of triggering and inhibitory signals, where MHC class I molecule
to curative effects. However, the clinical responses were not consistent and the attention
induce an inhibitory signal through the engagement of inhibitory receptors .
23
soon diverted to the overwhelming developments in other types of therapies that later the
standard of care, like surgery, radiotherapy and chemotherapy. In 1909, Paul Ehrlich
A second category of immune escape mechanism is the ability of cancer cells to express
developed a hypothesis that the development of tumors may be controlled by the immune
ligands of inhibitory receptor, immune checkpoint (IC) molecules, on their cell surface
9,10
system
11,12
who proposed
. This hypothesis was further developed by Thomas and Burnet
(Figure 1B). Asides from NK cells, many T cells also express inhibitory receptors. In the 1980’s
the theory of cancer immunosurveillance in 1957. They suggested that lymphocytes act as
CTLA-4 was discovered on activated effector T cells and regulatory T cells (T ) . CTLA-4
24
regs
guards and are responsible for recognizing and eliminating newly arising tumor cells that
competes with costimulatory receptor CD28 for B7 ligands and inhibits proliferation and
25
differ from normal host cells by their expression of tumor specific neo-antigens as a
IL-2 secretion by T cells by inhibiting T cell receptor (TCR) signal transduction via CTLA-4–
consequence of mutations. However, during the development of cancer, a
26 process
associated tyrosine phosphatase, SHP-2, resulting in dephosphorylation of TCR-ζ . PD-1
comprising sustained proliferation, evasion of growth suppressors, cell death resistance,
is another inhibitory receptor and was cloned in 1992 . Activation of the PD-1 gene was
27
suggested to be involved in apoptotic cell death induced on lymphocytes. The ligand of
13
replicative immortality, angiogenesis, metastasis and reprogrammed metabolism , tumor
PD-1 (PD-L1) is a member of the B7 gene family. PD-L1 is expressed by antigen presenting
14
cells finally manage to evade immune destruction . The process that leads to the evasion
cells (APCs), but also on nonlymphoid tissues like heart and lung tissue. As mice deficient
of immune elimination is later described as immunoediting, because this includes all phases
in PD-1 expression demonstrate autoimmunity , the interaction between PD-L1 and PD-1
28
of interaction between cancer and immune system beyond immunosurveillance .
15
determines a threshold for peripheral tolerance, autoimmunity and the extend of immune
responses at the site of inflammation in balance to the costimulation of CD28 by B7 .
29
By the expression of PD-L1, cancer cells embark on this natural tolerance threshold and
IMMUNE ESCAPE MECHANISMS OF CANCER
jeopardize immune attack. There are also tumor extrinsic mechanisms, including preventing
The immunoediting hypothesis is composed of three phases: elimination, equilibrium and
the infiltration of leukocytes, attracting immune suppressive cells and release of abundant
16
escape . This theory originates from microevolution in which the immune system selects
immunosuppressive cytokines 30,31 . Together, these escape mechanisms lead to the last
17
phase of immunoediting, which is the escape of tumor cells from immune control, ultimately
for tumor cells that are best adapted and thereby the least immunogenic . During the first
resulting in clinically detectable tumor lesions.
phase, the elimination phase, newly arising tumor cells are immunologically distinguishable
from normal cells by NK, CD4 and CD8 T cells by the expression of tumor specific neo-
Table 1. Classification of tumor-associated antigens 1-5
Table 1. Classification of tumor-associated antigens 1-5
Tumor antigens Examples
Differentiation antigens Melan-A/MART-1, tyrosinase, gp-100, carcinoembryonic
antigen (CEA), CD19 and NY-BR-1
Mutational antigens abnormal forms of p53, β-catenin, CDK4
overexpressed/amplified HER-2/neu, human telomerase reverse transcriptase
antigens (hTERT), epidermal growth factor receptor (EGFR)
cancer-testis (CT) antigens melanoma-associated antigen 3 (MAGE-A3), and NY-C0-58
and NY-ESO-1
viral antigens Human Papilloma Virus (HPV), Epstein Bar Virus (EBV) and
Merkel cell polyomavirus (MCV)

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