Download LESSON 4.4 WORKBOOK Why don’t we all die from cancer?

LESSON 4.4 WORKBOOK
Why don’t we all die from cancer?
Cancer is a rare event thanks to the activity
of the immune system, which is able to
eliminate more than 99% of all tumor cells.
This lesson will explain how the immune
system normally controls cancer cell growth
and metastases, and how in rare instances
cancer cells can actively subvert the immune
system and escape immune surveillance.
How does the immune system identify cancer cells?
The role of the immune system in preventing cancer is rarely discussed, but in fact the immune system
takes care of over 99% of tumor cells, killing them before they can become malignant. It is very rare that
a mutated cell is able to escape immune surveillance. You may remember from the Infectious Diseases
module that the immune system is tasked with protecting the body against foreign agents, such as pathogens and that the immune system is able to recognizes these pathogens as foreign because they express
antigens on their surface that immune cells detect as ‘non-self’. But cancer cells are different from foreign
pathogens in that they come from the host itself. What characteristics do they have that allows the immune
system to categorize them as ‘non-self’?
Wo r k b o o k
Lesson 4.4
As we well know, cancer cells are typically heavily mutated or express proteins not found in normal cells ­—
for example mature cells usually don't’ express the enzyme telomerase which prevents cells aging, while
cancer cells do. Similarly cancer cells revert to a less differentiated state to help them migrate in the stroma
and enter the bloodstream ­— this too is out of context. As the cancer cells acquires more mutations or
expresses more out-of-context proteins the odds of it being detected as ‘non-self’ increase.
MC Questions:
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1. True or False: Cancer cells express
mostly the same proteins as normal
cells, which is why the immune
system cannot detect them easily.
aa. True.
bb. False.
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LESSON READINGS
DEFINITIONS OF TERMS
MHC class I proteins (MHC
I) – proteins that present short
peptides of proteins made in a
cell on the surface of the cell to be
recognized by the immune system.
Immunosurveillance – the
principle that the immune system
is responsible for identifying and
killing cancer cells.
Innate immunity – the non-specific arm of immune system that
includes physical barriers, mucus
membranes, and NK cells.
The immune system detects cells as ‘self’ or ‘non-self’ by examining the small fragments of proteins
cells regularly present on their surface. When cells degrade their proteins with proteases, MHC class I
proteins (MHC is short for major histocompatibility complex) deliver these protein fragments to the cell
surface and present them on the outside world. Immune cells survey these protein fragments and, based
on their structure, decide whether they are ‘self’ or ‘non-self’. For example if a cell is infected with a virus
and makes viral proteins as a result, some of these viral proteins will be degraded and then presented
to the outside by the MHC. Passing immune cells will survey the virus protein fragments, determine that
they are ‘non-self’ and direct the virus-infected cell to be killed. The same is true for tumor cells, except
they aren’t infected. Instead MHC proteins present fragments of mutated or out-of context proteins on the
cell surface for immune cells to decide that they are ‘non-self’ and direct the cells to be killed. This kind of
immune system activity against cancer is called immunosurveillance.
Killing cancer cells
You may also remember that the two main branches of the immune system – innate and adaptive
immunity – play different roles. Innate immunity includes physical barriers such as the skin, and mucus
membranes that trap pathogens like bacteria that are trying to penetrate into the body. The innate
immune system located in these barriers contains cells that are able to kill anything they do not recognize, using a ‘shoot first, ask questions later’ approach to handling pathogens. In contrast a major role of
the adaptive immune system is to remember previous infections so that the body is prepared to handle
Adaptive immunity – the specific
arm of immune system recognizes
pathogens and mounts responses
based out of previous exposure.
Includes B and T cells.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.4
Figure 1: Antibodies that recognize 'non-self' proteins expressed on the
surface of cancer cells will bind cancer cells. These antibodies are bound
by NK cells, which are then activated and lyse the target cell by triggering
apoptosis.
similar pathogen threats in the future. The adaptive immune system is composed of two major types of
cells: B cells make antibodies and are most useful for dealing with external pathogens like bacteria, and T
cells that are most useful for handling internal pathogens like viruses.
MC Questions:
2. Where do the peptides that MHC I
proteins bind mostly come from?
(Circle all correct.)
aa. Proteins that are outside the cell.
bb. Proteins from pathogens.
cc. Proteins made within the cell.
dd. Signaling molecules.
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3. True or False: Mucus membranes
play an important role in preventing
cancer spread.
aa. True.
bb. False.
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LESSON READINGS
DEFINITIONS OF TERMS
Natural Killer (NK) cell – an
innate immune cell that binds to
antibodies to kill cells, or kills cells
that lack MHC I on the surface.
Cytotoxic T lymphocyte (CTLs)
– a type of T cell that is responsible for killing cells that express
non-self peptides bound to MHC I
on their surface.
Antibodies are chiefly present in mucus
and the bloodstream so they only play a
role in killing tumor cells found in these
areas. Antibodies recognize the cancer
cells and then use natural killer (NK)
cells to kill them. When an antibody
recognizes a specific antigen on a cell, it
attaches to it with its ‘arms’ leaving the tail
of the antibody - its so-called Fc portion
- protruding into space (see Figure 2). A
passing NK cell can interact with the Fc tail
of the antibody via its own Fc receptors.
The binding of the Fc receptors to the Fc
tail of the antibody, which itself is bound to
antigens on the cell surface activates the
NK cells so that they can tell the cancer cell
to initiate apoptosis.
Clonal expansion – the growth
of adaptive immune cells in
response to detection of a pathogen or cancer cell.
Figure 3: When NK cells detect
MHC on the surface of the cell, that
signals to inhibit NK cell killing activity.
When there is no MHC, NK cells are
active to kill the cell.
Wo r k b o o k
Lesson 4.4
MC Questions:
4. Which of the following is a way for
cancer cells to evade the immune
system? (Circle all correct.)
aa. Stop expressing MHC I.
bb. Surround themselves with other
cells.
cc. Trigger necrosis.
dd. Stop expressing oncogenes.
Figure 2: A cancer cell expressing a “nonself” peptide will bind a CTL, which will cause
replication of that CTL, called clonal expansion.
An increase in number of CTLs will allow for
immune killing of that tumor.
It is important to note that while the antibody interaction with the protein antigen because cancer cells
present protein fragments on their surface with MHC
like virus infected cells do, they are also targets of the
adaptive immune system, like virus infected cells are.
When the immune system surveys a cell infected with
a virus and decides it is ‘non-self’ it sends a cyotoxic
T cell (CTL) to kill it. CTLs resemble antibodies in
that they only recognize one kind of protein fragment presented by the MHC, just like each antibody
recognizes only one antigen. When a CTL identifies a
single ‘non-self’ protein fragment from the cancer cell it
also kills the cancer cell by inducing apoptosis, just like
the NK cell does.
Finally once an antibody has interacted with its antigen the B cell makes more antibodies (this is called
clonal expansion). In just the same way, once a CTL has recognized a tumor protein fragment on the cell
surface numbers also increase rapidly through clonal expansion. In this way CTLs can also cause many
cells in a tumor to die.
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5. 5. True or False: Immunoevasion is
an evolved trait developed in cancer
cells by random mutation.
aa. True.
bb. False.
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LESSON READINGS
MC Questions:
How cancer cells can escape the immune system
Given that all dividing cells accumulate mutations randomly it should not be surprising that cancer cells,
which are dividing more rapidly than most, may eventually acquire random mutations that will allow them
to avoid immune surveillance and escape immune system control. This is called immunoevasion. We
can identify three different categories of mutation that play these roles:
■■ Mutations that allow the cancer cell to hide its identity so it is no • longer recognized as ‘non-self’.
DEFINITIONS OF TERMS
■■ Mutations that allow the cancer cell to avoid the ‘die’ signal.
■■ Mutations that actually kill the immune cells.
Immunoevasion – the process
by which cancer cells attempt
to avoid immune detection and
attack.
CTL cells recognize cancer cells as ‘non-self’ because of the protein fragments they present on their
surface in conjunction with MHCI. These fragments may come from out-of-context proteins or mutated
proteins. Both can be reversed, but maybe at some cost to the tumor cell: For example we mentioned
tumor cells that are detected as ‘non-self’ because they produce telomerase out of context. Telomerase
repairs telomeres so the tumor cell does not age normally. Hence a tumor cell that no longer expresses
telomerase out-of-context will no longer be detected as non-self and therefore will not be targeted for
killing by the immune system. Unfortunately this does not mean it won’t die - it now may very well die due
to regular aging!
Tumors cells can take another tack to hide their identity: In
order to recognize protein fragments CTL cells need the
MHCI to present them properly on the tumor cell surface.
Cancer cells that no longer express MHCI can’t present the
fragments properly, so CTL cells won’t be able to detect
and kill them.
Wo r k b o o k
Lesson 4.4
The immune system uses NK cells to outsmart tumor cells
that no longer express MHCI. Unlike CTL cells, NK cells
use antibodies not MHCI to recognize surface protein. If
an antibody has bound to the ‘non-self’ fragment an NK cell
can swoop in and kill the tumor cell even though CTLs no
longer can.
Figure 5: Cancer cell
(brown) surrounds itself
with platelets (blue) to avoid
recognition in the blood stream
by NK cells.
6. Which of the following is a negative
effect for the cancer cell that is
attempting to evade the immune
system? (Circle all correct.)
aa. Decreased gene expression
leads to platelet binding.
bb. Decreasing oncogene
expression prevents growth/
survival of cancer cell.
cc. Evasion leads to more spreading
and less growth.
dd. Decreasing MHC I expression
makes cell sensitive to NK cell
attack.
7. Why do cancer cells not die when
exposed to death ligands?
aa. Membrane is resistant to
ligands.
bb. Apoptosis pathway in cells is
shut down.
cc. They make their own death
ligand.
dd. All of the above.
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LESSON READINGS
But cancer cells fight back! Most NK cells are found in blood and lymph, and tumor cells in the blood can
evade NK cells by surrounding themselves with platelets. Platelets are normally responsible for clotting
wounds, and large numbers are found in the blood. Tumor cells can surround themselves with a platelet
‘shield’ that guards against NK cells recognizing and attacking them.
DEFINITIONS OF TERMS
Platelets – a type of blood cell
responsible for clotting that is
present in very high numbers in
the blood stream, and can bind
to cancer cells to allow them to
evade the immune system.
Immune cells kill infected cells, and tumor cells by secreting signals known as death ligands which
interact with death receptors on the cells in question. Binding of the death ligand to the death receptor
activates the apoptosis pathway and the cell effectively commits suicide. This is normally an extremely
effective way to kill a damaged or infected cell. Unfortunately, as we well know, one of the earliest mutations that tumor cells acquire are mutations that inactivate the apoptotsis pathway by making it insensitive
to death signals and in this way promoting growth and survival. Tumors that have already acquired mutations in the apoptosis pathways will not be sensitive to immune killing, which is therefore most effective in
early stage tumors.
To make matters worse, tumor cells that are resistant to apoptosis sometimes flip the script on immune
control by synthesizing and releasing their own death ligands. These death ligands will be able to kill
nearby immune cells that have an active apoptosis pathway. If a CTL or NK cell attaches to a tumor cell
that is secreting death ligands it will be activated to apoptose.
Nonetheless the immune system can take care of a vast number of potentially problematic tumor cells
provided they are still able to apoptose. The tumors left are those able to subvert immune control and
become detectable.
Wo r k b o o k
Lesson 4.4
Notes:
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STUDENT RESPONSES
Immunotherapy is a recently developed strategy to treat cancers by boosting the body’s immune system. Can you give twothree examples of how the immune system could be improved to kill cancer cells?
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Remember to identify your
sources
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Wo r k b o o k
Lesson 4.4
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TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 4.4
DEFINITION
Adaptive immunity
The specific arm of immune system recognizes pathogens and mounts responses based out of previous
exposure. Includes B and T cells.
Clonal expansion
The growth of adaptive immune cells in response to detection of a pathogen or cancer cell.
Cytotoxic T lymphocyte
(CTLs)
A type of T cell that is responsible for killing cells that express non-self peptides bound to MHC I on their
surface.
Immunoevasion
The process by which cancer cells attempt to avoid immune detection and attack.
Immunosurveillance
The principle that the immune system is responsible for identifying and killing cancer cells.
Innate immunity
The non-specific arm of immune system that includes physical barriers, mucus membranes, and NK cells.
MHC class I proteins
(MHC I)
Proteins that present short peptides of proteins made in a cell on the surface of the cell to be recognized by
the immune system.
Natural Killer (NK) cell
An innate immune cell that binds to antibodies to kill cells, or kills cells that lack MHC I on the surface.
Platelets A type of blood cell responsible for clotting that is present in very high numbers in the blood stream, and can
bind to cancer cells to allow them to evade the immune system.
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