Page 11 - linda_borst

ROLE FOR THE IMMUNE SYSTEM IN CANCER

In 1891 Dr William Coley, often referred to as the “Father of Immunotherapy”, was the first
to search for a method to activate the immune system as an alternative treatment method
for sarcoma, after witnessing the painful death of an 18-year-old patient. For this, he used a
mixture of live and inactivated Streptococcus pyogenes and Serratia marcescens , leading
7,8
to curative effects. However, the clinical responses were not consistent and the attention
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
developed a hypothesis that the development of tumors may be controlled by the immune
system 9,10 . This hypothesis was further developed by Thomas and Burnet 11,12 who proposed Chapter 1
the theory of cancer immunosurveillance in 1957. They suggested that lymphocytes act
as guards and are responsible for recognizing and eliminating newly arising tumor cells
that differ from normal host cells by their expression of tumor specific neo-antigens as
a consequence of mutations. However, during the development of cancer, a process
comprising sustained proliferation, evasion of growth suppressors, cell death resistance,
replicative immortality, angiogenesis, metastasis and reprogrammed metabolism , tumor
13
cells finally manage to evade immune destruction . The process that leads to the evasion of
14
immune elimination is later described as immunoediting, because this includes all phases of
interaction between cancer and immune system beyond immunosurveillance .
15

IMMUNE ESCAPE MECHANISMS OF CANCER

The immunoediting hypothesis is composed of three phases: elimination, equilibrium and
escape . This theory originates from microevolution in which the immune system selects
16
for tumor cells that are best adapted and thereby the least immunogenic . During the first
17
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-
antigens (Table 1) resulting in elimination by the production and secretion of cytokines (e.g.
interferon (IFN)-γ, α and β, tumor necrosis factor (TNF)-α, Interleukin (IL)-12, IL-15, etc),
granzymes, perforins, and chemokines. Perforin or IFN-γ deficient mice, or rag2 deficient
mice lacking functional T cells, are much more susceptible to tumor development compared
to immunocompetent mice 18,19 . The phase of equilibrium is characterized by a balance
between tumor development and immune control, which might last as long as the lifetime
of the host. This has been validated by studies showing that administration of a low dose
carcinogenic substance to immunocompetent mice, induced tumor formation, but could
be controlled. However, if certain components of the immune system were corrupted, for
instance by antibodies depleting lymphocyte populations or cytokines, this disrupted the
established equilibrium .
20
Tumor cells that develop escape mechanisms to interfere with components of the
immune system themselves can also avoid elimination and tumor control. One of these
mechanisms is avoiding the recognition by the immune cells. Recognition of tumor cells
by CD8 T cells depends on the expression of classical MHC class I molecules to present
tumor antigens (Figure 1A). Antigen loss and loss or downregulation of MHC expression is

GENERAL INTRODUCTION 9