Cancer, Immunoediting and Immunotherapy Flashcards Preview

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Flashcards in Cancer, Immunoediting and Immunotherapy Deck (20)
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Describe the process of immunoediting.

1. Elimination
---Circulating T cells recognise tumour cells via tumour antigens
---T cytotoxic cells then kill tumour cells
---Elimination can be complete or partial

2. Equilibrium
---Rate of proliferation is equal to the rate of elimination, so that tumour size doesn't change

3. Escape
---Tumour cells proliferate too fast so that they escape the T cells


What are the different types of tumour antigens found on tumour cells?

1. Products of mutated genes (passenger mutations)

2. Mutated proteins as a result of oncogenes or mutated tumour suppressor genes (driver mutations)

3. Inappropriately expressed normal (i.e. non-mutated) proteins
---e.g. proteins normally only found in embryonic tissue

4. Viral antigens


How do T cytotoxic cells kill tumour cells?

1. T cytotoxic cells recognise tumour cells via MHC class I molecules
a. The T cytotoxic cell then kills the tumour cell

2. Antigen presenting cells recognise tumour cells via MHC class II molecules
a. APCs then present the tumour antigens to T helper cells
b. T helper cells then activate the T cytotoxic cells
c. T cytotoxic cells then kill the tumour cells

3. Sometimes tumour cells will express costimulatory factors
a. Costimulatory factors bind to the CD28 molecule on T cytotoxic cells
b. This causes complete activation of T cells


How do NK cells and macrophages kill tumour cells?

1. NK cells target cells that do not express any MHC molecules
a. Therefore, when tumour cells decrease MHC expression to evade T cells, NK cells will target them instead
b. NK cells then kill the tumour cells


How do tumour cells evade an immune response?

1. Tumour cells stop expressing antigens (“antigen loss variants”)

2. Tumours stop expressing MHC class I molecules

3. Tumours inhibit T cell activation, e.g. by:
a. PDL-1 expression
b. Loss of B7 costimulatory molecule expression on APCs

4. Tumour cells secrete immunosuppressive cytokines, e.g. Transforming growth factor beta (TGF beta)

5. Tumour cells lack costimulatory molecules

6. Tumours grow too quickly for the immune response to completely eradicate them


List the steps of the metastatic cascade.

1. Local invasion
2. Neovascularisation
3. Detachment
4. Intravasation
5. Transport in blood or lymph
6. Lodgement/arrest
7. Extravasation
8. Growth at ectopic sites


List the 7 features which allow tumour cells to metastasise.

1. Reduced cell-cell adhesion via E-cadherin
2. Reduced cell-substratum adhesion via integrins
3. Increased motility via HGF
4. Increased proteolytic ability via MMPs
5. Angiogenic ability via VEGF
6. Ability to intra- and extravasate
7. Ability to proliferate (locally and at ectopic sites)


Outline how E-cadherin might be lost in some cancers (including direct and indirect causes).

Direct loss of E-cadherin:
1. Exon skipping in diffuse-type gastric cancers (results in loss of Ca2+ binding domain, which is needed for cadherin-cadherin interactions)
2. Mutation in E-cadherin genes (e.g. via methylation)

Indirect loss of E-cadherin:
1. Mutations in proteins associated with E-cadherin, e.g.
a) Beta catenin
b) APC (adenomatous polyposis coli) - controls beta catenin levels
2. Mutations in transcription factors which control E-cadherin expression, e.g.
a) Snail
b) Slug
c) Twist


How might dysfunctional integrin molecules promote metastasis?

1. Decreased adhesion to the basement membrane
2. Increased migration of tumour cells through the stroma
3. Increased adhesion to blood vessel endothelium
4. Act as a binding site for proteolytic enzymes


How does HGF (hepatocyte growth factor) cause increased cell motility?

HGF interrupts E-cadherin mediated cell-cell adhesions
1. HGF is produced by stromal cells in a tumour

2. HGF binds to c-met on tumour epithelial cells
a) c-met is a tyrosine kinase receptor

3. Activation of c-met causes increased tyrosine kinase phosphorylation of beta catenin
a) This causes disrupted E-cadherin mediated adhesion


Describe the production of MMPs in the metastatic cascade.

1. Stimulated by tumour-stromal interactions, e.g.
a. Breast carcinoma cells release TGF alpha
b. TGF alpha acts on host stromal cells
c. Stromal cells release stromelysin 3

2. Pro-MMPs are activated by serine proteases, e.g.
a. Urokinase plasminogen activator (uPA) activates plasminogen to form plasmin
b. Plasmin binds to uPAR receptors on the cell surface
c. This activates pro-MMPs

3. Negative regulation by tissue inhibitors of metalloproteinases (TIMPs)


Describe the process of angiogenesis in tumours.

1. When tumours become too big, they require an independent blood supply and become hypoxic

2. Hypoxia stimulates the release of HIF (hypoxia-inducible factor)

3. HIF stimulates:
a. VEGF – binds to VEGFR on stromal cells and stimulates them to become endothelial cells
i. This forms new blood vessels
b. Pro-coagulants – stimulate fibrinogen to be converted into fibrin
i. This causes blood clotting


Describe intravasation/extravasation of tumour cells and the molecules involved.

1. Temporary cell-endothelial adherence causes tumour cells to “stick” to the endothelium

2. Cells can then move through the endothelium

3. Cell proteins involved:
a. L-selectin (tumour cell), which binds to:
b. Vascular addressins (tumour cell), which bind to:


Describe the MAP kinase/MAPK signalling pathway.

1. An extracellular mitogen binds to the tyrosine kinase receptors in the cell surface
a. Receptors that may be involved: EGFR, Trk A/B, Fibroblast growth factor receptor, PDGFR

2. This activates Ras

3. Ras activates MAP3K (e.g. Raf or B-Raf)

4. MAP3K activates MAP2K (e.g. Mek)

5. MAP2K then activates MAPK

6. MAPK then activates a transcription factor, e.g. MYC
a. This causes activation of the cell cycle


What are the main 3 targets of monoclonal antibodies in cancer treatment?

1. Tumour specific proteins
2. Over-expressed antigens
3. Blockage of inhibitory receptors (e.g. CTLA4)


What are the 4 ways in which monoclonal antibodies can kill cancer cells?

1. Induce apoptosis by blocking growth factor receptors on tumour cells

2. Complement activation

3. ADCC (antibody dependent cell cycle toxicity)
---If the tumour cell is covered with antibodies, it is more visible to the immune system

4. Antibody is conjugated with a toxin/radio isotope
---Binding of the antibody leads to binding of the toxin/radio isotope, which then kills the tumour cell


Outline the different types of non-cellular immunotherapy for cancer.

1. Monoclonal antibodies

2. PDL1 inhibitors

3. Cytokine therapy, e.g.
a. IFN alpha/beta
b. IL-2

4. Disease vaccines, e.g.
a. Bacilin Calmette-Guerin (BCG) vaccine
b. Imiquimod (TLR8 ligand)

5. Peptide vaccines, e.g.
a. Single peptide vaccine
b. Multiple peptide vaccines

6. Checkpoint inhibitor blockade

7. Bi-specific T cell engagers (BiTEs)


What are the 3 most common drugs used in cancer immunotherapy, and what type of drugs are they?

Vemurafenib (BRAF inhibitor)

Iplimumab (CTLA4 inhibitor)

Nivolumab (PDL1 inhibitor)


Give a specific example of targeted therapy in cancer.

Type of drug: tyrosine kinase inhibitor

Mechanism of action:
1. Normally Abl is a tyrosine kinase that phosphorylates proteins, leading to cell proliferation
2. Bcr-Abl mutations in cancer cause Abl to be constantly active, therefore cell proliferation is constantly stimulated
2. Imatinib inhibits Abl so that the signalling pathway is interrupted


Give some examples of classes of drugs that are used in targeted therapy for cancer.

VEGF inhibitors, e.g.