Immunity of Cancer Flashcards
Experimentally which form of tumour had the strongest immunological reaction?
- Carcinogen induced tumours - weakly immunogenic (creating immune response)
- Spontaneous animal tumours - weakly immunogenic
- Viral and UV-associated tumours - strongly immunogenic
What are some tumour cell characteristics?
- Tumour specific antigens
- Produce cytokines (eventually cause amplification of your immune response, so switch on and off things)
- Decreased MHC I (this is bad because you the tumour will basically become invisible to T cells and so will not be killed)
What are the different types of tumour antigens and how they are formed? How does the immune system distinguish neoplastic (tumour cells) from normal cells?
Normally you produce lots and lots of self-proteins because you have a nucleus and the nuclear proteins sit around in your cytosol and they get expressed on the surface of this MHC.
- If the proteins start to become mutated, they are also expressed on the MHC and are recognised as foreign
- If you find that the tumour starts making things, so it’s not the tumour itself but a product of the tumour, this will also be expressed on the surface
- If you have an over expressed protein, so a tumour starts making too much or a slightly weird version of it, that is also recognised and ultimately if it’s a virus then it is fairly easy to recognise
- Hepatitis will give you liver cancer. Hepatitis virus is very easy to spot because it’s a virus, it’s not you
- Classification of tumour antigens base on their patterns of expression:
Tumour-specific antigen (TSA) – tumour produces these
Tumour-associated antigens (TAA) – not the tumour itself but the things associated with it
What is our innate immune response to tumours?
Innate immune response to tumours is vast and comes down to the 4 key players in the diagram. You have cytotoxic T cells have the capacity to go out, hunt down tumours and kill them. There are macrophages which are eating cells. Natural killer cells; kill without makeup and they do not require an MHC to bind. They are amazing in cancer. They kill cancer cells because if there is an antibody is made to a tumour, it binds to NK cells and in doing so, allow the NK cells to kill the tumour.
NK Cells
Macrophages
- Tumour associated macrophages(TAMS)-20% of tumour tissue
- Source of cytokines & chemokines that recruit other cells
Neutrophils
- Perforin & Granzyme
- ROS, Proteases calprotectin o Cytokines & chemokine
How do natural killer cells work?
It has been found that people that have poor NK function have lots of metastatic cancers
Absence of NK (Beige mouse) increase in spontaneous tumours. Metastatic cancer associated with abnormal NK function
Spontaneously cytolytic for tumour cells – this means that they spontaneously kill cancer cells very effectively and therefore they do not need the MHC molecule and T cell receptor to function
MHC/TCR independent
NK cells have an FC receptor that binds to the bottom end of an antibody. Antibodies work by having 2 arm sections which are the antigen binding fragments. If you produce antibodies that bind to tumour, things are going to happen to that tumour and one of them is that NK cells have the capacity to bind to the FC fragment of the antibody. So, if you have anti-tumour antibodies, the NK cells can bind to them
NK cells work in the same way as the TK cells – through apoptotic mechanism, so they melt the tumour by through enzymes onto it. The tumour cell dies away and you find that these are very good for sweeping up any cells that have escaped T cell killing
T cells go around and target & kill cells but for those tumours that have down regulated their MHC, the NK cells can essentially come along with that antibody that can bind and then NK cells can come and sweep it up
How is the innate and adaptive immune system linked in an immunological response to cancer?
- Presentation of antigen is the same in the cancer as in a normal infection
- Tumor antigen expressing cells are phagocytosed by professional antigen presenting cells- like dendritic cells
- It then migrates up to the lymph where it will meet the T cell
- The antigen presenting cells ‘presents’ the antigen to the T cells causing their activation
- These activated T cells will produce B cells, T helper cells, killer cells out of the lymph node and kill the cells expressing that tumour antigen
What is the role of cytotoxic T cells in an adaptive immune response to tumour cells?
- Cytotoxic T lymphocytes (CTL) can control tumours in the tumours’ early stages, but by the time we detect a tumour clinically the tumour is almost always resistant to the immune system.
- How big is the tumour in its early stages, before it starts to get blood vessels? Literally a couple of cells. The maximum a tumour can grow without blood supply is 2- 3 mm. this is why when you can looking for cancer, so for example in breast cancer, testicular cancer, you are looking for a grain of rice, not a melon sticking out from the side of your body.
What is the significant of interferon gamma in an adaptive immune systems response to cancer?
- T helper cells independently of helping the cytotoxic cells, also do things to tumours
- They release a cytokine called IFN-γ and its been shown that if you have a severely compromised immunodeficient (SCID) mouse, so no T cells, B cells etc.
- If you took another mice and transferred its of CD4 cells (T cells) into SCID mice confers protection against tumours
- Neutralising IFN-γ abolishes this protection
- IFN-γ receptors on tumour not involved
What is the role of antibodies and B cells in an adaptive immune response to tumour cells?
- B cells produce antibodies which promote death & destruction and bind to NK cells
- High titres of anti-tumour IgG found in cancer patients
- igG is the anti-cancer antibody, so you are producing antibodies against cancer which are circulating around in your body which are clearly not doing a good job
- Auto antibodies also found (antibodies against self)
- Therefore; Monoclonal Abs a valuable treatment for cancer
- They can activate the compliment pathway (it’s a protein produced from your liver that crumbles and essentially formulates pathways 1 – 9 and does a lot of different things. It is an anaphylatoxin, it activates membrane attack complexes and it can act as opsonic fragments)
- Classical pathway
- Role of classical complement pathway not yet established
How does the complement system respond to tumour cells?
- It promotes phagocytosis through opsonisation. Presence of an antibody makes it more tasty to a phagocyte
- Activation of the complement system (it’s a little protein, an antibody comes along, it completely degrades and ultimately causes anaphylatoxins big inflammatory responses and making holes in the tumour, formation of membrane attack complexes. As a result, the inside of the tumour explodes)
- It can activate NK cells through their FC receptors, this is called antibody-dependent cellular cytotoxicity. So, in the presence of an antibody, NK cells can bind and therefore kill
What are factors that can interfere with the recognition and lysis of tumour cells by T lymphocytes?
Tumour factors:
- lack of antigen or MHC expression
- dysfunction of antigen presentation
- release of immunosuppressive factors such as IL-10, TGF B and VEGF
- tumours can counter attack the immune system using fas ligands of their own
- blockage of antigen receptors on the surface of tumour cells
Immune System factors:
- immune ignorance to tumour cells
- lack of tissue homing molecules and/or defective adhesion
- t-cell regulation dysfunction. T-cell regulator cells would down regulate immune response to infection so the more T cell regulators a patient has the less likely they will fight a cancerous infection effectively
- Immunosuppression
What is immunotherapy?
Immunotherapy is a type of treatment that stimulates the body’s immune system to fight the cancer. Immunotherapies are used to fight cancer or to control side effects from other cancer treatments.
What are some types of immunotherapies for tumours?
- Vaccination with tumour antigens
- Augmentation of host immunity to tumours (ramp up what we already have)
- Passive Immunotherapy for tumours with T cells and antibodies
How does immunotherapy work?
- Enhancing the body’s immune system to stop or slow tumour growth.
- Boost the killing power of immune system cells (T, NK and Macrohages)
- Prevent cancers from spreading to other parts of the body
- Changing cell signals that allow tumour growth.
- Making tumours more susceptible to an immune system attack.
- Once researchers better understand the growth and spread of tumours, they will be better able to identify patients who may benefit from immunotherapies.
- Currently, cancer vaccines are the type of immunotherapy that present the most innovative and potentially effective treatment for cancer.
What are some potential benefits of cancer vaccines?
- Use the body’s own immune defence mechanisms
- Provide an alternative to or enhance the efficacy of standard chemotherapy
- Create minimal side effects
- Preventive vaccines against virus-associated cancer (HPV, EBV)
