L18: Tumour Immunology Flashcards
Which mouse study proves that tumours are immunogenic
1) inject a carcinogen to a mouse
2) this causes a tumour in that mouse
3) take the live tumour cells and grow it in a lab
4) give the tumour cell to a different mouse and the mouse will also develop a tumour
5) if you irradiate the tumour cell so they cannot divide and vaccinate to another mouse and then give the live tumour cell the mouse will remain tumour free
Describe the mouse experiment that shows tumours can induce immunological memory
1) inject a carcinogen to a mouse
2) mouse develops cancer
3) surgically respect the tumour and collect the tumour cell
4) if you give the tumour cell to a different mouse it will grow a tumour
5) if you give the tumour cell back to the original mouse the mouse will remain tumour free
In mouse experiments is tumour protection seen in mouse with T cell deficiency
No
If we do not have protection against tumour when there is T cell deficiency what does this indicate
That T cell plays a key role in protecting cancer
What is the concept of immunosurvelliance
The immune system recognises precursors of cancer and destroys the precursor of cancer before they become clinically apparent
What is the concept of cancer immunoediting
Immune system edits the immunogenicity of tumours that may form
What are the 3 Es of cancer immunoediting
Elimination
Equilibrium
Escape
What is elimination
Immune mediated destruction of cancer cells
What is equilibrium
Immune system is able to control the outgrowth of tumours but cannot eliminate the tumour cells
What is escape
Tumour mutated variant forms is no longer controlled by the immune system as the cells selected in the equilibrium phase grow out
What MHC complex doeS CD8 T cells detect
MHC1
What MHC complex does CD4 T cells detect
MHC2 complex
Where can MHC complex be found
Antigen presenting cells i.e tumour cells
What does the MHC complex bind to
T cell receptor
When the MHC complex binds to a T cell receptor what happens
A signal is delivered to the T cell so it becomes activated = signal 1
After signal 1 one what signal occurs
Signal 2
How does the T cells receive signal 2
CD80/CD86 on APC binds to CD28 on T cells
What can signal 2 be like
Positive co-stimulation
Negative co-stimulation
Give an example of positive co-stimulation in signal 2
CD80/CD86 binding to CD28 on T cell
Give examples of negative co-stimulation
- CD80/CD86 binds to CTLA-4 (on T cell)
- PDL1/2 bins to PD-1 (on T cell)
What does the positive co-stimulation do
Activate the T cell
What does the negative co-stimulation do to the T cell
Suppress
Does CD28 or CTLA-4 binds strongly to CD80/CD86
CTLA-4
Overall what regulates the activity of T cells
Both positive and negative co-stimulation
If a T cell can recognise a tumour antigen describe how it will occur
1) tumour antigens are released
2) antigen is picked up by dendritic cells
3) dendritic cells drains to lymph nodes
4) dendritic cells present the antigen to T cells
5) if one of the T cells have appropriate receptor for the antigen, the T cell will clonal expand
6) T cells will leave lymph node into the blood to reach tumour site and destroy it
What are the tumour associated antigens that can be present for a T cell to recognise
Mutated self proteins generated by dna damage
Overexpressed self proteins
Lineage specific antigens
Abnormal post translational modification of self protein
Viral proteins
Antigens in the tumour stroma
What does the tumour have to be like so we can target it with immunotherapy
Tumour specific : so we don’t destroy health cells
Antigen shared amongst different tumour : so we can target many cancer
Critical for tumour growth
Antigen to which immune system is not tolerant
What are the 2 types of immune tolerance
Central tolerance
Peripheral tolerance
What is the central tolerance
In the thymus when positive selection (binding to MHC complex) and negative selection (binding to self antigen) occurs
What is peripheral tolerance
When any auto reactive T cell that escapes the thymus will be inactive when it interacts with self proteins
Why is tolerance important
Cancer develops from our own tumour cels so immune system will be tolerant to it, if a antigen that you are not tolerant to occurs then you can destroy the cell
Normally how does a cell process MHC class 1
1) proteins are synthesised in the cytoplasm of the cell
2) proportion of proteins will be Brocken into fragments by proteasome
3) fragments are transported into the ER by TAP transporter so protein is associated to MHC 1
3) MHC 1 becomes exported to the cell surface membrane
Additionally when T cells engage with APC what stabilises the interaction
Molecular interactions (adhesion molecules)
When would a T cell not be able to detect the tumour cell
When there is a interference with: MHC processing Molecular interactions (adhesion molecules) that stabilise the T cell interaction
What are the mechanism when tumours can escape immune responce
Loss of MHC 1 expression
Reduced expression of molecules e.g TAP transporter involved in antigen presentation
Loss of co-stimulatory expression e.g CD80/CD86
Loss of adhesion molecules
Loss of target antigen
Inhibiting T cell infiltration
Immunosupression at tumour site
What are the 2 ways of inhibiting T cell infiltration to tumour sites
1) endothelins b receptor on the tumour epithelium signals to prevent modulation of ICAM on vascular endotherlium to T cell cannot adhere to the vasculature
2) nitrosylation of chemokines that attract T cells so T cells aren’t attracted
What are the ways of immunosuppression at the tumour site
- Tumour cell expresses immunosuppressive cytokines
- t reg cells
- myeloid derived suppressor cells
What is the role of t regulatory cells
Control normal T cells so they are not out of control
What can high number of t reg do
Play a role in immune escape
What are myeloid derived suppressor cells
A heterogenous cells of myeloid origin that have myeloid progenitor cells, immature macrophages, granulocytes and dendritic cells
What happens to myeloid derives suppressor cells during cancer
Expand
In cancer what does myeloid derived suppressor cells increase
Immune suppressive factors called arginase 1 and iNOS
What does arginase 1 and iNOS metabolise
L-arginine
What does loss of l-arginine inhibit
T cell proliferation
What are the 3 T cell based therapies for cancer
Non specific T cell stimulation
Vaccination
Adaptive T cell therapy
What does non-specific T cell stimulation involve
The use of immunostimulatory cytokines (toxic)
Blockage of immunologic checkpoints
Describe the blockage of immunologic checkpoints
1) administer antagonist antibody
2) antagonist antibody binds to CTLA-4 (negaitve co-stimulatory molecule of T cell function)
3) blocking CTLA-4 means CD28 can bind to CD80/CD86
Name an antagonistic antibody used in non specific T cell stimulation to target CTLA-4
Ipilimumab
What cancer is ipilimumab used in
Melonoma
Name another antagonist antibody that blocks PD1 binding to PDL1/2 on tumour cells for negaitve co-stimulation
Pembrolizumab
What cancer is pembrolizumab used in
Melonoma
In vaccination what do we give
Irradiated tumour cell
Protein antigens
Dendritic cell based vaccines
What does adaptive T cell therapy involve
1) Injecting T cells from patient or a donor
2) T cell expands to give lots of T cells that target the tumour antigen
In what cancer is adaptive T cell therapy used in
Melonoma
How do we generate T cells rapidly
1) A T cell receptor gene is transferred to a T cell
2) T cell codes for the specific receptor and targets the cancer
What are the potential side effects of T cell based therapy
Autoimmunity
Make tumour worse by enhancing angiogenesis
What are the other treatments in cancer
Monoclonal antibodies
What does antibodies recognise
Antigens on cell surface
What are the mono-clonal antibodies immune mediated mechanism
1) antibody mediated lysis
2) Antibody dependent cellular cytotoxicity
How does complement mediated lysis work in monoclonal antibody
1) The antibody binds to target antigen
2) Complement cascade is activated
3) MAC is produced
4) MAC punches a hole in the cell so lysis occurs
What is antibody dependent cellular cytotoxicity (ADCC)
1) antibody bind to the antigens
2) NK cells recognise the antibody
3) NK cells kill the tumour cell
What are the direct effects of monoclonal antibodies in cancer therapy
1) blocking receptor ligand interaction
2) prevent angiogenesis
3) cytotoxic activity of conjugated antibodies
How does monoclonal antibodies prevent angiogenesis
Bind to agonist E.G Vegf
What is cytotoxic activity of conjugated antibodies
Antibody delivers toxic molecule to the tumour such as radionuclide
