Module Four: Cancer Immunology Flashcards
What is the fundamental prediction hypothesis?
Immunodeficient individuals should display a dramatic incidence in tumour incidence
Who published the paper which demonstrated no difference in cancer incidence between nude mice and normal mice?
Osias Stutman
Transgenic animal studies reveal that tumour elimination requires
Interferon-gamma, perforin, TRAIL, Type 1 INF (INF alpha/beta)
And the following effector cells:
Innate immunity: NK cells, NKT cells, gamma/delta T cells
Adaptive Immunity: CD8 T cells (cytotoxic T Cells)
What are the three E’s of immunoediting?
Stage 1: elimination (immunosurveillance)
Stage 2: equilibrium
Stage 3: escape
What is transformation?
The process of a cell becoming carcinogenic/malignant
What does MIC activate?
NKG2D on NK cells
Release perforin
What causes the activation and maturation of dendritic cells?
The presence of tumour cells and tumour antigens initiates the release of danger cytokines such as INF alpha and heat shock proteins
CD8 T cells present antigen to what?
Class One MHC
What is the anecdotal evidence for immune reactivity to tumours in humans?
- autopsy studies reveal that incidence of tumours may be much greater than incidence of cancer
- spontaneous regression of established tumours have been reported
What is the more direct evidence for immune reactivity to human tumours
- Immunosuppressed transplant recipients have increased incidence of non-viral cancers
- Cancer patients can develop spontanous adaptive and innate responses to their tumours
- The presence of tumour inflitrating lymphocytes is often a positive prognostic indicator of survival
Evidence of equilibrium
Cancers that come back in transplant patients
How to sustain equilibrium?
- Cellular dormancy
- Angiogenic dormancy
- Immune dormancy
What are the tumour escape mechanisms?
Low immunogenicity
Antigen modulation
Immune suppression by tumour cells or regulatory T cells
Induction of lymphocyte apoptosis
How do tumour cells induce apoptosis in T lymphocytes?
FAS activation
Cancer cells express FAS ligand and bind to FAS receptor on T lymphocytes leading to apoptosis
What is immunotherapy? And who are the key players?
Treatment of disease by inducing, enhancing or suppressing the immune system.
Dendritic cells, B cells and T cells
How do we induce an adaptive immune response?
Antigen
Effector cells (CD4 and CD8)
Antigen presenting cell
Immune target (pathogen/ tumour)
How do APCs present antigen?
Class one (endogenous I.e. Inside out) Class Two (exogenous I.e. Outside in) Dendritic cells
What are the three signals for T cell activation?
Signal One: MHC:: TCR interaction
Signal Two: co-stimulation: CD80/86::CD28 interaction
Signal Three: competitive inhibition or co-stimulatory signals: CTLA-4 out competes CD28 for binding to CD80/86
Types of cancer immunotherapy?
Adoptive cell transfer
Vaccination
Monoclonal antibodies
Immune modulators
Examples of adoptive cell therapy
Lymphokine activated killer therapy
Tumour infiltrating lymphocytes therapy
Genetic modifications of TILs
Increase TCR avidity to target
Chimeric Ag receptors
Transgenic approach (humanised mouse) - useful against colon cancer and melanoma
Pros of TIL
ACT can eradicate tumours
GE modification to increase avidity/ specificity and helped identify best ACT cell populations
Potential for personalised medicine
May compliment other treatment modalities
Cons of TIL therapy
Limited to patients that tolerate pretreatment conditioning
Most successful in melanoma - not applicable to all cancers
Not FDA approved
Expensive and laborious - requires specialised training and facilities
Examples of anti cancer vaccines
Whole tumour cell vaccines Peptide vaccines Pathogen vector vaccines GM tumour cell vaccines DNA vaccines Fusion vaccines (tumour cells/ antigen + APC) Prime boost vaccines
What was the first FDA approved therapeutic vaccine to treat cancer?
Spiuleucel T (Provence) For chemo refractory metastatic prostate cancer
What is a 223 AA protein that is expressed on activated lymphocytes?
CTLA-4
What are the function properties of CTLA-4?
In vitro X-linking with CTLA-4 inhibits T cell proliferation
Blockade of CTLA4 with soluble intact Fab fragment promotes T cell proliferation
soluble anti-CTLA-4 fab fragments enhance T cell responses to Peptide AG
CTLA-4 KO mice exhibit severe T Cell proliferative disorders
What are the two FDA approved humanised anti-CLTA-4 monoclonal antibodies ?
Ipilimumab (IgG1)
Tremelimumab (IgG2)
Role of PD -1
Maintains peripheral tolerance and prevents autoimmunity
Issues with immunotherapy
Not all cancers respond as well as melanoma
Side effects: colitis, skin and endocrine side effects
Cost
What is a cold tumour?
Have very little inflammatory cells
Enriched in immunosuppressive cytokines
High numbers of Treg cells and MDSC
What are hot tumour cells
Enriched in Thelper 1 Chemokines
High number of effector immune cells high number of functional APCs
What do tumour specific CD8 T cells need to recognise on the surface of tumour cells before they will mount an attack?
Antigens
Why isn’t recombinant interferon used much in cancer patients today?
It makes them too sick
And quality of life is diminished
How do you identify tumour specific antigens (neo-antigens)?
Next generation sequencing
How many nucleotides in the full human genome?
6 billion
What is the name of the component that codes for proteins
Exome
How many nucleotides code for protein?
1-2%
How many nucleotides code for an amino acid?
3
Which tumours are the most highly mutated and which have the lowest mutational burdens?
Lung cancer/ melanoma - most highly carcinogens
Vs
Childhood
What is the ATTAC cancer trial?
Antigen-targeted therapy against cancer
Steps of ATTAC cancer program
Cancer patient => tumour sampling and bio banking => gene sequencing => neo antigen prediction => advance T cell monitoring => next generation immunotherapy => systems biology => animal models => novel clinical trials
