Tumour immunology Flashcards
Describe what happens in a woman with breast cancer who goes on to develop paraneoplastic cerebellar degeneration?
They will present with vertigo, unintelligible speech and truncal and appendicular ataxia. Anti-CDR2 antibody detected in serum and detection of breast cancer/ The woman amounted an immune response against breast tumour and this immune response resulted in degeneration of cerebellum- it also causes elimination of purkinje cells in the brain. The antigen is normally expressed in neural tissue but in breast cancer is expressed and immune response is against antigens in neural breast which leads to against neural as well
What does PCD teach us?
Certain tumours can express antigens that are absent from corresponding 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, it may result in auto-immune destruction of normal somatic tissues
What evidence is there to show immune control of human tumours?
Autopsies of accident victims have shown that many adults have microscopic colonies of cancer cells with no symptoms of disease
Patients treated for melanoma, after many years free of disease, have been used as sources of organs for transplantation. Transplant recipients have developed tumours
What is the concept of immunosurveillance?
Malignant cells are generally controlled by the action of the immune system
What is the first stage of the cancer-immunity cycle?
Release of antigens from cancer cells
What happens to the cancer cell antigens after release?
They are captured by APCs (e.g. dendritic cells) which then migrate to local draining lymph nodes
What is required for activation of T cell response?
Environment is sufficiently inflammatory and there is enough costimulation
What does activation of the T cell response bring about?
An antibody response
Why are T cells particularly important in immune responses against tumours?
Antigens are intracellular
What do the T cells do after being activated?
They go back to the tumour (tumour infiltrating T cells), they recognise the processed tumour antigens and then kill the cancer cells
Give a brief summary of the 7 stages of cancer immunity cycle
Release of cancer cell antigens Cancer antigen presentation Priming and activation Trafficking to T cells to tumours Infiltration of T cells into tumours Recognition of cancer cells by T cells Killing of cancer cells
How does the cancer immunity cycle lead to a form of natural selection?
If there is a good immune response against the tumour and T cells kill the tumour cells, this applies a selection pressure for variants of tumour cells that can evade killing by T cells so certain cells have survival advantage and will proliferate
What happens when T cells have been exposed to an antigen several times?
They express the PD-1 receptor
What do tumour cells do in response to expression of PD-1 receptor by T cells?
They upregulate expression of the ligand PDL-1 which can bind to the PD-1 receptors and downregulate the T cell response
What can help stimulate T cell responses against tumours?
Blockade of PD1-PDL1
What is cancer pathogenesis and the initiation of cancer like?
It usually results from multiple sporadic events over time. Aberrant regulation of apoptosis and cell cycle results in tumour growth
What is the difference between viral infection and tumour?
Viral infection- Lots of pattern recognition receptors, lots of cytokines and lots of inflammation- up regulation of costimulatory molecules and immune response is surmounted
Tumour cells are not very inflammatory so they are more likely to be missed by immune system
What happens when there is sufficient inflammation in a tumour?
There will be recruitment of innate immune cells (dendritic, macrophages and 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
What is required for activation of an adaptive anti-tumour immune response?
Local inflammation in the tumour (stimulates expression of costimulatory molecules)
Expression and recognition of tumour antigens
What problems are there in immune surveillance of cancer?
It takes the tumour a while to cause local inflammation
Antigenic differences between normal and tumour cells can be subtle
What is the principle of cancer immunotherapy?
It looks at conditioning a patient’s immune system so that it’s better able to stimulate an immune response that can be effective against the tumour
What do MHC class I molecules present?
Endogenous peptides on their cell surface for recognition by T cells- shows the T cells what’s going on
What happens to MHC presentation in the absence of infection?
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
What can be presented by MHC molecules in tumour cells?
Tumour specific antigens
Certain viruses are associated with tumours, name a couple
EBV and HPV
When do opportunistic malignancies (of viral origin) occur?
During immunosuppression
Give some examples of opportunistic malignancies and when they occur?
EBV-positive lymphoma- post-transplant immunosuppression
HHV8-positive Kaposi sarcoma- HIV
HTLV1 associated leukaemia/lymphoma
HepB virus and HepC virus associated hepatocellular carcinoma
HPV-positive genital tumours
What do tumour cells in cervical cancer express?
Viral proteins- Tumour specific viral antigens. The immune system can detect these and kill them
What induces and maintains cervical cancer?
E6 and E7 oncoprotein of HPV
What are E6 and E7 oncoprotein?
Intracellular antigens
What happens to peptides from E6 and E7?
They are presented by MHC on cell surface.
What do vaccines for HPV use/not use and why?
They don’t use E6 and E7 oncoprotein (because it 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)
How do most people respond to HPV?
Most people generate a good immune response against HPV and have no problems and no tumours
What happens to the small minority of patients that don’t have a good immune response against HPV?
They don’t generate a good T cell response and could go on to have immune failure and leads to development of neoplasia
When can HPV vaccination be given?
Preventative vaccination
Therapeutic vaccination
What are tumour associated antigens generally derived from?
Normal cellular proteins to which the immune system is not tolerant and they become immunogenic when expressed by the tumour
Give some examples of tumour associated antigens?
Cancer-testes antigen- not expressed in normal adult tissues except male germ cells
MAGE- melanoma associated antigens- identified in melanoma and other tumours
What is frequently mutated and overexpressed in human cancer?
P53
What can P53 mutation and overexpression lead to?
Loss of cell cycle control
What are the two things that P53 be considered as?
Tumour associated antigen- when it is overexpressed
Tumour specific antigen- when it becomes mutated
What can the single amino acid change in p53 be recognised by?
CTLs
What can mice be immunised with?
Peptides derived from p53
What do you need to add to generate a T cell response in mouse that has been immunised?
An adjuvant- this will cause the inflammation and costimulation necessary for the immune response
What happens to the spleen cells taken from the mice?
The CTLs are cultured and transferred back to the animals with tumours. This can cause almost complete destruction of the tumour- very powerful
What are T cell responses against p53 like?
Weak because it is a self peptide- that’s why powerful adjuvants are needed
Why might even the adjuvants not be capable of generating an immune response ?
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
What is an issue with cancer immunotherapy?
Tolerance- 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 are abnormally expressed). so most people have developed tolerance against the tumour associated antigens
How can immune responses against tumour associated antigens lead to autoimmune type problems?
The tumour associated antigens are normal proteins that are expressed elsewhere in the body as well- it might be good at dealing with cancer but could cause autoimmunity.
What does treating melanoma by stimulating immune responses frequently cause?
Local auto-immune depigmentation in melanoma patients
What are two major obstacles for targeting of tumour-associated auto-antigens for T cell mediated immunotherapy of cancer?
Autoimmune responses against normal tissues
Immunological tolerance
- Normal tolerance ot autoantigens
- Tumour induced tolerance
What are the three approaches for tumour immunotherapy?
Cancer “vaccination”- Immunisation to stimulate natural anti-tumour responses
Genetic modification of a patient’s own T cells to express a receptor capable of recognising the tumour
Blockade of molecules that inhibit T cell responses e.g PD-1/PD1L1
How does genetic modification of T cells work?
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 T cells can kill tumour cells
The receptors are chimeric antigen receptors- consists of normal intracellular signalling domain of the T cell receptor and a single chain antibody on the outside
