Cancer Immunology Flashcards
What is central tolerance and peripheral tolerance?
Self-reactive T cells are eliminated during development (central tolerance)
T cells are inactivated in the periphery (peripheral tolerance)
Give 3 examples of antigens derived from self-molecules that escape T cell tolerance (3 points)
- Cancer/testis antigens (CTag)
- Differentiation antigens
- Oncofoetal antigens
What are Neoantigens? (1 point)
Antigens derived from genes mutated in the cancer
- Any gene with a coding sequence changed from the wild-type has the ability to be a neoantigen
Where are cTag antigens found and what do they play a role in? (2 points)
Cancer/testis antigens (CTag) - found in developing testes - play a role in malignancy - MAGE molecules
What are differentiation antigens, and where are they found? (2 points)
Differentiation antigens - expressed at low levels in normal development - but greatly increased in tumour cells - e.g., tyrosinase in melanoma
- Are antigens derived from self-molecules that escape T cell tolerance mechanisms
Where are oncofoetal antigens found? And what are they?
2 points
Oncofoetal antigens - expressed during embryonic development before T cell development - e.g., CA125 - Carcinoembryonic antigen (CEA)
Name 2 other cancer-specific alterations in proteins
2 points
- Changes in post-translational modifications (MUC family molecules)
- Aberrant splicing products (generating new coding sequence)
Name the three types of tumour associated antigens
3 points
- Antigens derived from self-molecules that escape T cell tolerance mechanisms
- Neoantigens
- Other cancer-specific alterations in proteins
What is NY-ESO-1?
- New York oesophageal squamous cell carcinoma
- Generates both antibody and T cell responses
What are the 3 E’s?
Elimination, equilibrium, escape
- Thought to be how the immune system sculpts cancer
Name 4 viruses that have evolved mechanisms to prevent MHC 1 molecules from reaching the surface
(4 points)
- Herpesviruses
- HPV 16 and 18
- Adenoviruses
- HIV
What two receptors do NK cells have?
2 points
- Killer inhibitory receptors - binds to MHC1 and turns off NK cell
- Activating receptor - e.g., NKG2D - kills cell and releases pro-inflammatory cytokines
How do NK cells target tumours? (2 points)
- Cell division of cancer cells drives cell cycle genes and presents surface ligands e.g., NKG2D
- Accumulation of NKG2D overcomes the MHC1 signal and so the NK cell is activated and targets the cancer cells
How do tumours evade immunity? (9 points)
- Loss of antigen
- Loss of MHC1
- Loss of activating ligands - e.g., NKG2D
- Recruitment of suppressive immune cells - e.g., Treg, M2-like macrophage and Myeloid Derived suppressor cells (MDSC)
- Secretion of immunosuppressive cytokines - IL-10, TGF-beta
- Metabolic competition with tumour cells
- Secretion of inhibitory metabolites
- Apoptosis of immune cells
- Initiation of immune checkpoints
What are immune checkpoints? (2 points)
- Naturally occurring feedback inhibitors of an immune response - e.g., PD-1
- Checkpoint molecules inhibit the T-cell and self limit the immune response - prevents killing of healthy cells
What does IFN-gamma/oncogene activity do to tumour cells? (2 points)
- IFN-gamma induces PD-L1- (ligand for PD-1) on tumour cells
- This inhibits T cells from PD-1-PDL-1 interaction - even if the correct antigen and T-cell receptor is present
What does TGF-beta do for tumours? (1 point)
- Counteracts immune cells brought to the tumour after T cell activation.
Three examples of immunotherapy of cancer (3 points)
- Antibody targeting of tumour cells
- T cell targeting of tumour cells
- Inhibiting immune checkpoints with antibodies
What is rituximab (anti-CD20) and how does it work?
3 points
- Treatment for lymphoma - also used for arthritis
- Is a chimeric therapeutic antibody - Fc receptors on NK cells recognise IgG and induce Antibody dependent cellular cytotoxicity (ADCC)
- Triggers complement pathway - initiates complement mediated cytotoxicity (CMC) - kills tumour
What is CD20? (2 points)
- A marker on B-cells - shows normal healthy B-cells
- Cross linking of CD20 induces apoptosis and sensities to chemotherapy
Brief explanation of T cell retargeting (3 points)
- Uses chimaeric antigen receptor (CAR) T cells
- Replace T cell receptor with different antigen receptor - and activated using antibodies
- T cells are injected back into patient and now express new receptor and mediate anti tumour activity
What are the problems with CAR T cells? (4 points)
- Logistics - need to be specifically made for each patient
- Very expensive
- Toxicity - T cells are very powerful and CAR T cells have bypassed the normal safeguards for self-reactivity
- Adverse effects are common - and can be life threatening
How does the immune checkpoint blockade work?
4 points
- Blocks the interaction between PD-1 and PDL-1
- Can use antibody against either PD-1 or PDL-1
- Used for other immune checkpoints also
- Wakes T cells up and allows them to continue to kills tumour cells - only activation signal
