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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: ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 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. 136 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. ________________________________ ________________________________ ________________________________ 3. True or False: Mucus membranes play an important role in preventing cancer spread. aa. True. bb. False. ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 137 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. ________________________________ ________________________________ ________________________________ 5. 5. True or False: Immunoevasion is an evolved trait developed in cancer cells by random mutation. aa. True. bb. False. ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 138 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. ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 139 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: ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 140 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? _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ ____________________________________________________________________________________________________ Remember to identify your sources _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ Wo r k b o o k Lesson 4.4 _____________________________________________________________________________________________________ ___________________________________________________________________________________________ 141 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. 142