Cancer immunology Flashcards
What was the evidence that the immune system controls cancer?
- Cancer immunosurveillance proposed in 50s and 60s, experimental evidence was lacking
- Early immunodeficient mouse models cast doubt on immune system controlling tumours, this fell out of favour
- Better immunodeficient mouse models due to gene targeting provided conclusive evidence of anti-tumour immunity
- Higher incidence of cancer in immunocompromised patients is consistent with this.
What are tumour related antigens called
Tumour associated antigens (TAAs)
What the TAA types
Cancer/testis antigens (CTag)
Differentiation antigens
Oncofoteal antigens
Cancer/testis antigens can be reativated in many tumour types, example of family of molecules
MAGE family molecules
Are differentiation antigens expressed more in tumours, give example
Expressed at very low levels in normal development (maybe below immune detection) but greatly increased in tumour cells like tyrosinase in melamona.
Oncofoetal antigens are expressed when, give example
Expressed during embryonic development before T cell development like carcinoembryonic antigen (CEA)
Define neoantigen, give examples
Antigens derives from genes in the cancer
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Such as Ras and p53 mutations, fusions and potentially any gene with a coding sequence change from the WT
Other cancer-specific alterations in proteins include
PTMs like MUC family molecules
Aberrant splicing products
For something to be called an antigen it needs to be detected by what
Antigen receptors
Why do we get cancer?
Elimination –> Equilbirum –> Escape
How can tumours evade the immune system (MHC)
Remove MHC class I and so T cells are useless
How do pathogen infected cells without MHC Class I still get detected
NKs have KIRs (imhibitory receptors) for MHC Class I and detect its lack so release IFN-gamma and TNF
How do TUMOUR cells without MHC class I get detected through NKs
There is a cell dividing (possible tumour), more transcription factor E2F which drives cycle genes, the E2F also switch on NKG2D activating ligands leading them to accumulating, NKG2D ligands will outweigh MHC I molecules, leading to tipping of the scale towards activation leading to NK cell killing even WITH MHC I present in this case due to excess of activating ligand.
What the principle cytotoxic effectors acting against tumout cells
CD8+ T cells and NK cells
How do NK cells kill cell targets
NK cells forms synapse and releases gramzymes (pro-atoptic enzymes) and perforin which perforate the target cells.
How can tumours evade immunity, list several examples
- Loss of antigen
- Loss of MHC class I
- Loss of activating ligands (e.g. for NKG2D)
- Secretion of immunosuppressive cytokines e.g. IL-10, TGF-Beta
- Recruitment of suppressive immune cells e.g. Treg, M2-like macrophage and Myeloid derived suppressor cells (MDSC)
- Metabolic competition with tumour cells
- Secretion of inhibitory metabolites
- Apoptosis of immune cells
- Initiation of immune checkpoints
Role of M1 macrophage
Mop up bacteria
Role of M2 macrophages
Fix wounds, immunosuppresive
Immune checkpoints are….
Naturally occuring feedback inhibitors of immune response. Discovered by studying T cell responses to viral infection.
What is the 6-step method of action of PD-1 immune checkpoint
- T cell encounters tumour
- Gets activated and kills tumour
- Releases IFN-gamma
- Upregulated PD-1
- Moves onto the next cell
- T cell now inhibted via PD1-PDL1 interaction
What is PD-L1 on tumour cells induced by . What does this lead to for the T cell
PD-L1 on tumour cells in induced by oncogene activity and/or IFN-gamma from T cells.
T cell becomes exhausted
Three ways to exploit anti-tumour activity of immune system to treat cancer
- Ab targetting of tumour cells
- T cell targetting of tumour cells
- Inhibiting immune checpoints with Abs
Antibody-based targetting of tumour cells does what to immunity
Redirect immunity to tumour cells
Rituximab is anti-______ and to treat l_______
anti-CD20, lymphoma
