Tumour Immunology Flashcards
How can breast cancer be linked to: severe vertigo, unintelligible speech, truncal and appendicular ataxia?
Paraneoplastic cerebellar degeneration
Explain how breast cancer can lead to the degeneration of the cerebellum.
Antigen the immune response is directed against is normally expressed in neural tissue (only expressed in breast tissue when tumorous)
Abnormal expression of this antigen in the breast triggered an immune response, which then also attacked the normal antigens in neural tissue –> destruction of purkinje cells in the cerebellum
Describe the cancer-immunity cycle.
Tumour cells die/ release antigens
Antigens are captured by APCs, which then migrate to local draining lymph nodes
If environment is sufficiently inflammatory + there is enough co-stimulation there will be activation of the T cell response
Once activated T cells return to the tumour– the processed antigens are recognised + killed by the T cells (releasing more antigens thus the cycle continues)
Describe the effect of the PD-1 – PDL-1 signalling on the T cell response.
After repeated exposure to an antigen, T cell starts to express PD-1 receptors
Tumour cells upregulate expression of PDL-1 ligand, which can bind PD-1 receptor + downregulate the T cell response
Blockade of PD1-PDL1 interaction could help stimulate the T cell response
(removal of the negative regulator= immune checkpoint blockade)
What is the main difference between tumours and viral infections with regards to the immune response?
Viral infections trigger lots of inflammation, causing upregulation of co-stimulatory molecules so an immune response can take place
Tumours don’t cause much inflammation, especially early on so 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 - “danger signal”
Expression + recognition of tumour antigens
What are the main problems with the immune surveillance of cancer?
Takes a tumour a while to cause inflammation
Antigenic differences between normal + tumour cells can be very subtle
Which MHC class presents endogenous peptides?
MHC Class I
Give 2 examples of opportunistic malignancies.
EBV positive lymphoma (post-transplant immunosuppression)
HHV8 positive Kaposi sarcoma (occurs in HIV)
Give 3 examples of viral infections that can cause cancer inimmunocompetent individuals.
HTLV1 associated leukaemia/lymphoma
HepB virus- + HepC virus-associated hepatocellular carcinoma
HPV positive genital tumours
Which oncoproteins of HPV are responsible for the induction and maintenance of cervical cancer?
E6
E7
What proteins do the vaccines for HPV use?
Surface proteins are used to generate virus like particles
Give an example of an HPV vaccine.
Gardasil 9
What are the 2 different times at which vaccines can be given?
Prophylactic vaccination (before disease) Therapeutic vaccination (to control disease once it has occurred)
What are tumour-associated antigens?
Normal cellular proteins which are aberrantly expressed (wrong location/ time/ quantity) in the tumour
Immune system needs to overcome tolerance to respond
Give 2 examples of tumour-associated antigens.
Cancer-testis antigens (developmental): 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 is it 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 2 major obstacles for the targeting of tumour-associated antigens in immunotherapy of cancer?
Autoimmune responses against normal tissues Immunological tolerance (not having self-reactive repertoire available to begin with or tumour inducing tolerance by releasing down regulatory factors)
What are 4 possible approaches to tumour immunotherapy?
Antibody- based therapy Therapeutic vaccination Immune checkpoint blockade Adoptive transfer of immune cells (combinations of any of the above)
List 4 examples that evidence immune control of tumours
Microscopic tumours in healthy adults causing no symptoms
Recipients of organs from cured melanoma patients develop melanoma
Immunosuppression increases risk of malignancy
Men twice as likely to die from cancer than women- women have a stronger immune response
In what case may the cancer immunity cycle be ineffective?
Any tumour cell that survives immune recognition e.g. via MHC down regulation, will be selected for, proliferate + escape immune destruction
What is the function of MHC class I and II?
I (all nucleated cells): Present endogenous antigens that originate from cytoplasm
II (on APCs): Present degraded peptide of pathogen antigen
What is a tumour specific antigen?
Antigen only found in tumour cells
