Tumour Immunology and Immunotherapy of Cancer Flashcards
Role of immune the system: summarise evidence for the importance of tumour surveillance by the immune system
- Certain tumours can express antigens that are absent from (or not detectable in) corresponding normal tissues that the tumour is derived from
- The immune system can, in principle, detect abnormally expressed antigens and, as a result, launch an attack against the tumour
- In certain cases, this may result in auto-‐immune destruction of normal somatic tissues
Evidence for immune control of tumours in humans
- Autopsies of accident victims have shown that many adults have microscopic colonies of cancer cells, with no symptoms of disease. Immune control?
- Patients treated for melanoma, after many years apparently free of disease, have been used as donors of organs for transplantation. Transplant recipients have developed tumours. Donor had developed ‘immunity’ to the melanoma, but the transplant recipients had no such ‘immunity’.
Cells involved:
- T cells have -> ab T cell receptor ->MHC restricted
- B cells have-> B cell receptor (antibody) vast range of molecules
Describe the cancer-immunity cycle
- The first step involved the release of antigens from the cancer cells
- These antigens are captured by professions APCs (e.g. dendritic cells), which then migrate to local draining lymph nodes
- If the environment is sufficiently inflammatory and there is enough costimulation then you will get activation of the T cell response
- Activation of the T cell response will also bring about an antibody response
-T cell responses are particularly important in immune responses against tumours because the antigens are intracellular - Once the T cells have been activated, they go back to the tumour (tumour infiltrating T cells)
- The processed tumour antigens are then recognised by the T cells, which can then kill the cancer cells
This cycle is pretty similar to viral infections
- If you amount a good immune response against the tumour and the T cells kill the tumour cells, this is applying a selection pressure for variants of the tumour cells that, for whatever reason, can evade killing by T cells (this is like antibiotic resistance)
7. So the cells that have a survival advantage in being able to evade killing by T cells survive and proliferate -‐ this is a form of natural selection
8. When T cells have been exposed to an antigen several times they express the PD-‐1 receptor
9. Tumour cells then upregulate expression of the ligand PDL-‐1 which can bind to the PD-‐1 receptors and downregulate the T cell response
10. Blockade of PD1-‐PDL1 interactions could help stimulate T cell responses
Explain how immune responses to tumours have some similarities with those to virus infected cells
- Initiation of cancer usually results from multiple sporadic events over time
- Aberrant regulation of apoptosis and the cell cycle results in tumour growth
- The difference between tumour and viral infection is the amount of inflammation (particularly right at the start)
Mutations occurs which result in tumour growth
Viral Infection -‐ lots of pattern recognition receptors, lots of cytokines and LOTS OF INFLAMMATION -‐ you get upregulation of costimulatory molecules and an immune response is surmounted
Tumour cells, especially if there are relatively few cells, are NOT very inflammatory so they are more likely to be missed by the immune system
- Once there is sufficient inflammation, there will be recruitment of innate immune cells (dendritic cells, macrophages, NK cells)
- Dendritic cells will capture antigens from the tumour cells and go to draining lymph nodes and present them to recirculating T cells
- This will be followed by recruitment of adaptive, antigen-‐specific immunity
Summary of requirements for activation of an adaptive anti-‐tumour immune response:
- Local inflammation in the tumour
- Expression and recognition of tumour antigens
NOTE: the inflammation is necessary to stimulate the expression of costimulatory molecules
Problems in Immune Surveillance of Cancer
- It takes the tumour a while to cause local inflammation
- Antigenic differences between normal and tumour cells can be very subtle
Principles of Cancer Immunotherapy
- Patients who have cancer will not have generated good immune responses against their tumours
- There hasn’t been enough inflammation or expression of antigen to trigger an immune response
- Immunotherapy looks at conditioning a patient’s immune system so that it is better able to stimulate an immune response that can be effective against the tumour
Tumour specific antigens
Tumour Specific Antigens
- MHC class I molecules present endogenous peptides on their cell surface for recognition by T cells
- This shows the T cells what’s going on inside the cell
- Even in the absence of infection, self peptides are constantly being loaded on the MHC molecules and being presented on the surface of the cells
- In tumour cells, if there are tumour specific antigens, these can be presented by MHC molecules
- Viral proteins are often the easiest to understand
Tumour specific antigens:
- Certain viruses are associated with tumours e.g. EBV and HPV -‐ these can be presented on the cell surface
- Sometimes mutated cellular proteins are presented on the cell surface
Chromosomal translocations might generate new combinations of protein sequences that are presented by MHC molecules
bcr and abl fusion creates a new sequence – another way of generating novel proteins
Cancers of Viral Origin OPPORTUNISTIC malignancies -‐ immunosuppression
- EBV-‐positive lymphoma: post-‐transplant immunosuppression
- HHV8-‐positive Kaposi sarcoma: HIV
It can occur in immunocompetent individuals
- HTLV1 associated leukaemia/lymphoma
- HepB virus-‐ and HepC virus-‐associated hepatocellular carcinoma
- HPV-‐positive genital tumours
Tumour cells in cervical cancer express viral proteins so these are tumour specific viral antigens
The immune system can detect these tumour cells and can kills them
HPV and Cervical Cancer
HPV and Cervical Cancer
- Cervical cancer is induced and maintained by the E6 an E7 oncoproteins of HPV
- These oncoproteins are intracellular antigens
- Peptides from these oncoproteins are presented by MHC on the cell surface
- The vaccines for HPV do NOT use the E6 and E7 oncoproteins (because that is responsible for inducing and maintaining cervical cancer) so they use structural proteins to generate virus like particles
- Gardasil is one of the HPV vaccinations
- Most people generate a good immune response against HPV and they have no problems and no tumours
- For a small minority of patients, they don’t generate a good T cell response and they could go on to have immune failure and lead to the development of neoplasia
The vaccination can be given at two different times:
- Preventative vaccination
- Therapeutic vaccination -‐ try to control the disease once it has occurred
Tumour antigens: explain the concept of tumour-associated antigens giving named examples, and explain how they differ from tumour-specific antigens
Tumour Associated Antigens
- These are generally derived from normal cellular proteins to which the immune system is not tolerant, and they become immunogenic when expressed by the tumour
- This is abnormal expression of a normal cellular protein
Examples of these antigens:
- Cancer-‐testes antigens -‐ not expressed in normal adult tissues except male germ cells (some expressed in the placenta)
- MAGE -‐ melanoma associated antigens -‐ identified in melanoma, also expressed in other tumours
- (HER 2: human epidermal growth factor receptor 2: overexpressed in very many cancers)
- Carcinoembryonic antigen CEA: normally only expressed in foetus/ embryo)
Tolerance induction by negative selection in the thymus: central tolerance – We all have T-cells capable of recognising cell proteins but in most people they don’t cause disease because they do not get activated
P53 and Cancer
This is frequently mutated and overexpressed in human cancer
- It can lead to the loss of cell cycle control
- P53 can be considered either:
- Tumour Associated Antigen -‐ when it is overexpressed
- Tumour Specific Antigen -‐ when it becomes mutated
- This is an example of how you can get both types of antigen in the same protein
- The single amino acid change in p53 can be recognised by CTLs
Immunotherapy experiments
Immunotherapy against melanoma in mice is accompanied by auto-immune skin depigmentation (vitiligo)
- Mice can be immunised with peptides derived from p53
- To generate a T cell response we need to add an adjuvant -‐ this will cause the inflammation and costimulation necessary for the immune response
- The spleen cells are taken from the animal and the CTLs are cultured and transferred back to the animals with tumours
- This can cause almost complete destruction of the tumour -‐ it is very powerful
- T cells responses against p53 will be WEAK because it is a self peptide -‐ that’s why powerful adjuvants are needed
- Even the adjuvants may not be capable of generating an immune response because the specificity just isn’t there in the repertoire of T cells because T cells that react with self antigens would have been deleted during selection in the thymus
Tolerance is an issue in cancer immunotherapy
- With central tolerance, T cells that react strongly with self are deleted via negative selection
This means that there is usually tolerance against tumour associated antigens (as these are just normal proteins that are abnormally expressed)
So most people have developed tolerance against the tumour associated antigens
Tumour Associated Antigens and Autoimmunity
- If you do generate an immune response against tumour associated antigens, this could cause autoimmune type problems because the tumour associated antigens are normal proteins that are expressed elsewhere in the body as well
- So the immune reaction may be good at dealing with the cancer, but it could cause autoimmunity
- There has been a lot of work done on treating melanoma by stimulating immune responses (‘cancer vaccination’)
- This frequently causes local auto-‐immune depigmentation in the melanoma patients
- Targeting of tumour-‐associated auto-‐antigens for T cell mediated immunotherapy of cancer
TWO major obstacles:
- Auto-‐immune responses against normal tissues
- Immunological tolerance
- Normal tolerance to autoantigens
- Tumour-‐induced tolerance
Immunotherapy: summarise approaches being used and developed for tumour immunotherapy, including antibody-based therapy, tumour vaccination and immune checkpoint blockade
1. Monoclonal antibody: single specificity
- “Naked” antibody
- “Conjugated” antibody – targeted to the tumour
- “Bi-specific” antibody - using DNA genetically engineered technology
Issue with all these methods is COST – benefit analysis
2. Cancer vaccination -‐ if we can identify some tumour specific antigens then we can develop a cancer vaccination
- We immunise the patients with the epitopes and a adjuvant to try and stimulate their natural anti-‐tumour responses
3. Genetic modification of T cells
- CD8 T cells are taken out of the patient and genetically modified to express a receptor that recognises particular tumour antigens
- These are then inserted back into the patient so that the T cells can kill the tumour cells
- The receptors are chimeric antigen receptors -‐ consists of the normal intracellular signalling domain of the T cell receptor and a single chain antibody on the outside
4. Blockade of molecules that inhibit T cell responses
Trying to remove the inhibitory influences rather than directly stimulating T cell responses – 2 pathways that are targeted are CTLA-4 and DP-1
It uses antibodies to block these interactions
5. “Personalised” tumour-specific cancer vaccines
- You can compare sequences and decipher what abnormalities exist in the tumour cells and decipher which proteins bind to the patient HLA molecules – way of making personalized vaccine
- It has been used successfully in research settings – not routinely used as it is incredibly expensive but in theory we CAN make tumour specific vaccines
6. ADT helping the patient by boosting the antibodies of the patient against the tumour – you can also engineer the antibodies to change
7. Chimeric Antigen Receptor (CAR) – usual type of receptor – just a single polypeptide chain – fused onto normal transmembrane part of T cell receptor and comstimulating T-cells and zeta chains come from three polypetpides
