Tumour Immunology Flashcards
How can breast cancer be linked to the following symptoms: severe vertigo, unintelligible speech, truncal and appendicular ataxia?
Paraneoplastic cerebellar degeneration
Explain how breast cancer can lead to the degeneration of the cerebellum.
The antigen that the immune response is directed against is normally expressed in neural tissue
It is only expressed in breast tissue when there is a tumour
The abnormal expression of this antigen in the breast was noticed and an immune response was mounted, which then also reacted with the normal antigens in the neural tissue –> destruction of purkinje cells in the cerebellum
Describe the cancer-immunity cycle.
Antigens are released from cancer cells normally after apoptosis and captured by APCs, which then migrate to local draining lymph nodes
If the environment is sufficiently inflammatory and there is enoughcostimulation then you will get activation of the T cell response
Once the T cells are activated they go back to the tumour – the processed antigens are then recognised by the T cells, which then kill the cancer cells
NOTE: this cycle is pretty similar to viral infections
Describe the effect of the PD-1 – PDL-1 signalling on the T cell response.
When a T cell has been exposed to an antigen several times, it starts to express PD-1 receptors
Tumour cells then upregulate expression of the PDL-1 ligand, which can bind to the PD-1 receptor and downregulate the T cell response
Blockade of the PD1-PDL1 interaction could help stimulate the T cell response
Problem with cancer immunity cycle that helps cancer develop
Immune selection pressure - any cancer cell that develops to not express antigen detected by immune system will evade immune control
What is the main difference between tumours and viral infections with regards to the immune response?
Viral infections trigger a lot of inflammation, which causes upregulation of costimulatory molecules so an immune response can take place
Tumours do not cause very much inflammation, especially early on so they are more likely to be missed by the immune system
What are the requirements for activation of an adaptive anti-cancer immune response?
Local inflammation in the tumour
Expression and recognition of tumour antigens
What are the main problems with the immune surveillance of cancer?
It takes a tumour a while to cause inflammation
Antigenic differences between normal and tumour cells can be very subtle
Which MHC class presents endogenous peptides?
MHC Class I
Give two examples of opportunistic malignancies.
EBV positive lymphoma (post-transplant immunosuppression)
HHV8 positive Kaposi sarcoma (occurs in HIV)
Give a few examples of viral infections that can cause cancer inimmunocompetent individuals.
HTLV1 associated leukaemia/lymphoma
HepB virus- and HepC virus-associated hepatocellular carcinoma
HPV positive genital tumours
Which oncoproteins of HPV are responsible for the induction andmaintenance of cervical cancer?
E6
E7
What proteins do the vaccines for HPV use?
Structural proteins are used to generate virus particles
Give an example of an HPV vaccine.
Gardasil
What are the two different times at which vaccines can be given?
Preventative vaccination (before the disease) Therapeutic vaccination (try to control the disease once it has occurred)
What are tumour-associated antigens?
They are normal cellular proteins to which the immune system is not tolerant and become immunogenic when expressed by the tumour
This is abnormal expression of a normal protein- in terms of timing location or quantity
Give examples of tumour-associated antigens.
Cancer-testis antigens – silent in normal adult tissues except male germ cells
MAGE – melanoma-associated antigens – identified in melanoma, also expressed in other tumours
When is p53 considered a tumour-associated antigen and when isit considered a tumour specific antigen?
Tumour-associated antigen – when it is over-expressed
Tumour specific antigen – when it becomes mutated
Describe the problem with tolerance in cancer immunotherapy.
T cells that react strongly with self are deleted (central tolerance) so most people have tolerance against tumour-associated antigens
What are the two major obstacles for the targeting of tumour-associated antigens in immunotherapy of cancer?
Autoimmune responses against normal tissues
Immunological tolerance
What are three possible approaches to tumour immunotherapy?
Cancer vaccination – immunisation to stimulate natural anti-cancer responses
Genetic modification of T cells to express a receptor capable of recognising the tumour – these are then inserted back into the patient so that the T cells can kill the tumour cells
Blockade of molecules that inhibit T cell responses
Evidence for immune control of tumours
Autopsies of adults who have died prematurely eg in an accident have colonies of cancer cells with no symptoms suggesting that there was immune control
Patients treated for melanoma who have gone on to donate organs in transplantation. The recipients of these have then gone on to develop melanomas suggesting there was some sort of immune control
Deliberate immunosuppressive increases the risk of malignancy
Men have much greater chance of dying from cancer than women who typically are able to mount much stronger immune response
Immunotherapy does enhance immune responses to cancer
Use of immune checkpoint blockade
With immune response there are many regulatory molecules which have inhibitory and stimulatory effects on response. Immunotherapy can act to inhibit these stimulatory molecules or enhance effects of inhibitory ones
Aims of some immunotherpaies
If the requirements for activation of adaptive anti-tumour response isn’t met can we teach adaptive immunity to selectively detect these cells
Examples of tumour specific antigens
Viral proteins of viruses which cause cancer
Mutated cellular proteins
How does monoclonal antibody therapy work
Antibodies are given which attach to specific antigens initiating an immune response against those cells
3 types of monoclonal antibody therapy
Naked - plain antibody given
Conjugated- is attached to something else( for example a radioactive particle or another drug)
Bi-specific- engineered to combine 2 specificities where binds to two antigens
Example of naked monoclonal antibody therapy
Trastzumab
What is trastzumab anti
HER2
CD20
CD52
EGFR
Example of conjugated monoclonal antibody therapy
Ibritumomab which is an anti CD20 antibody attached to yttrium 90
Example of bi specific monoclonal antibody therapy
Blinatumomab
What is blinatumomab
Anti CD3 and CD20
Used in B cell tumour therapy
Example of therapeutic cancer vaccination
Provenge- anti prostate cancer
How does provenge work
Patients own WBC are treated with a fused protein between prostatic acid phosphatase and cytokine GM-CSF. An adoptive treatment so cells are put back into the body of patient and DC maturation is improved as well as enhancing PAP specific T cell responses
Pathways targeted in immune checkpoint blockade
CTLA-4 and PD-1
How does adoptive transfer of cells work
T cells are removed from patient (normally from tumour removed after surgery), cultured and grown then put back in body to enhance response
How does chimeric antigen receptors work
Ends of antibodies specific to an antigen are removed and added to T cell receptors from T cells removed from patient
