L14 - Cancer immunology Flashcards
What type of lymphocytes do many human cancers contain?
tumour infiltrating lymphocytes (TILs)
If tumours are self tissue, how are they detected?
Tumour associated antigens (TAAs)
Types of TAAs?
proteins escaping T-cell tolerance mechanisms: CTag, differentiation antigens, oncofoetal antigens
Neoantigens
other cancer specific alterations in proteins
What are CTag?
found in developing testes
MAGE family molecules
What are Differentiation antigens?
expressed at low level in normal development
greatly increased in tumour cells
What are Oncofoetal antigens?
expressed during embryonic development before T cell development
What are Neoantigens?
derived from mutated genes in cancer
e.g. p53 mutations
What are other cancer-specific alterations in proteins?
changes in post-trans mods
aberrant splicing products
Can you have an Ab response without T cells?
It is very difficult
What are 3 E’s of cancer immunoediting?
- Elimination
- Equilibrium
- Escape
What happens in the elimination phase of cancer?
When tumours arise in tissue - immune cells can recognise and eliminate
What happens in the equilibrium phase of cancer?
tumour cells arise more resistant
variety of tumour variants develop
What happens in escape phase of cancer?
one variant may escape killing mechanism - or recruit regulatory cells to protect it = spread
How can tumours evade T cells?
T cells can only see antigen in context MHC class I
without MHC class I - T cells are useless
How can a cell lacking MHC class I be spotted?
NK cells destroy self-cells lacks MHC class I
What are the inhibitory receptors that NK cells have for MHC class I?
Kiler inhibitory receptors (KIRs)
WHat is the balance of signals for NK cells?
KIR (neg) and NKG2D (pos - activating receptor)
What happens to ligands when MHC class I is lost?
E2F transcription factors - drive cell cycle AND expression of ligands of NKG2D
What mechanisms do tumours use to evade immunity?
Loss of MHC class I
Loss of activating ligands (NKG2D)
Secretion of inhibitory metabolites
Apoptosis of immune cells
Initiation of immune checkpoints
What 3 things happen when a T cell recognised a virus-infected cell via MHC class I and T cell receptor?
T cell kills infected cell
T cell makes pro-inflammatory cytokines
T cell expresses immune checkpoint molecules (PD-1) that inhibit T cell and self-limit immune response
Mode of action of the PD-1 immune checkpoint?
T cell encounters tumour
activated - kills tumour
release IFN-y
upregulates PD-1
moves to next cell
T cell now inhibited via PD-1-PDL1 interaction
What is PD-L1 on tumour cells induced by?
oncogene activity
IFN-y (from T-cells)
Ligand of PD-1?
PD-L1
3 types of immunotherapy for cancer?
Antibody targeting of tumour cells
T cell targeting of tumour cells
Inhibiting immune checkpoints with antibodies
How does antibody-based targeting of tumour cells work as an immunotherapy?
REDIRECTS IMMUNITY TO THE TUMOUR CELLS
NK cells - Fc receptors, ADCC when recognise clustered IgG
complement-mediated destruction of B cell - CMC
cross linking of CD20 induces apoptosis
name of antibody-based targeting of tumour cells immunotherapeutic agent?
Rituximab (chimaeric)
How is T cell activity retargeted using CAR T cells?
replace T cell receptor with different antigen receptor based on an scFv antibody (fragment of variable region)
joined by linker - join to transmembrane and signalling domain that can act in T cells
What are CAR T cells?
Chimeric Antigen Receptor T cells
Problems with CAR T cells?
logisitics
cost
toxicity
What is ICB (Immune checkpoint blockade) cancer treatment?
add antibody against PD-L1 to break inhibitor action
stops T cells receiving neg signals
now only get pos signals - enable attack of tumour cells
