Tumor Immunology II Flashcards
Eerst lecture Mandy, dan college II Sonja
What are the seven steps of the tumor-immunity cycle?
- Tumor ag release
- Ag-uptake by DC
- T-cell priming
- T-cell trafficking
- T-cell infiltration
- Ag-recognition
- Tumor killing
Why can T cells traffic into the tumor?
Because they are primed with tumor antigens
Name three examples how tumors can inhibit T cell killing
- Checkpoints presented in tumor tissues
- Thick stromal layer
- Inhibition of the number of DCs that present antigen in the LN
Name two ways by which antigen presentation by DCs can be enhanced to boost the anti-tumor immune response?
- In vivo targeting
- Adoptive transfer of ex vivo loaded and activated DCs
At which step of the tumor immunity cycle does DC-therapy interfere?
T cell priming in the LN
Why can DC-therapy lead to a more effective anti-tumor immunity cycle?
Because they are primed
What are ways to manipulate DCs in- or ex vivo? Administration of? (3)
- DC-activating factors
- DC-mobilizing agents
- Antigens/adjuvant
Why can we not make a vaccine based on the DC subsets that we isolate from the peripheral blood?
Only few DC subsets are present in the peripheral blood
Which cells are used for DC vaccines?
Monocyte-derived DCs
Which compound can be used to mature DCs?
Growth factors; GM-CSF
How long does it take to create one DC vaccine?
10 days
How are DCs loaded with antigens?
Antigen pulsing
What is meant with an “autologous setting” in DC vaccination?
You use tumor material from the mice/patient itself
What is meant with an “allogeneic setting” in DC vaccination?
Material that is used to load DCs is not genetically identical to the material that is present within the patient
Which allogeneic setting approach can be used for DC vaccine formation?
Tumor cell lines of multiple patients -> mix them
How can we further enhance DC-therapy efficacy? (2)
- Targeting TAM phenotype
- Combination with checkpoint blockade
What are TAMs?
Tumor-associated macrophages -> present within tumor tissue
Which phenotype are TAMs associated with?
Suppressive phenotype -> inhibit anti-tumor response
What are the three main mechanisms by which TAMs can inhibit the immune system?
- Direct suppression T cells
- Induce Tregs
- Inhibit DC maturation
What is the goal of using antibodies to block the PD1/PD1L axis?
Better activation and function of T cells
Why is the dogma that the PD1/PD1L axis is only important in the tumor site not really valid anymore?
Axis also present within the TDLN -> can hamper T cell priming by DCs
Which two in vivo DC targeting approaches did Sonja zoom in on in her second lecture?
- Synthetic long peptides
- mRNA vaccines
Why do you often need a proliferation step for immune monitoring of vaccine responses?
Often T cells in the blood are of low frequency
What are the different assay you can use for immune monitoring of vaccine responses? (4)
- IFNy ELISA
- IFNy ELISPOT
- Flow cytometry
- Changes in TCR clonality/diversity
Which assay can be used directly ex vivo for immune monitoring of vaccine responses? Why?
ELISPOT -> sensitive
What is indicative of a nice and potent response upon vaccination?
Clear result directly ex vivo using ELISPOT
How can you determine which cells make the cytokine using ELISPOT?
Sort them in advance
Which subset of patients benefits from a vaccine that broadens the T cell repertoire?
Some patients have low clonality to begin with
What is the main advantage of using SLPs as vaccination strategy?
Shelf life of several years
What is Sonja’s opinion on the usage of SLP vaccines? Which purpose seems ideal?
Generic vaccines
What is Sonja’s opinion on the usage of mRNA vaccines? Which purpose seems ideal?
Personalized vaccines
What is the main aim of the development of therapeutic vaccines for chronic HBV infection?
Getting rid of all antigen and DNA in the blood
What can be said about the T cell response in chronic HBV infection?
Very low T cell responses (mostly exhausted)
What causes the very low (exhausted) T cell responses in HBV infection? (2)
- Antigen overexposure
- Lack of effective priming
How does an UV-based in vitro HLA binding assay work? (6)
- Loading HLA complex with UV cleavable peptide
- Expose to UV
- Peptide broken down
- Peptide falls out of complex -> complex falls apart
- Expose complex to to peptide of interest
- If the peptide can bind, it rescues the falling apart -> takes place of UV cleaved peptide
Why do we not have to predict epitopes for HLA-II?
HLA-II is present at such an ambiguous level -> we get them for free
Which areas of a viral genome can you best use for epitope mapping to develop a SLP-based vaccine (HBV)?
Areas on the viral genome that the virus needs to propagate -> will be conserved
Why are chronic HBV patients responding better to SLP-vaccination than resolvers?
Resolvers could have cleared disease a long time ago -> memory population very small
SLP design is based on..? (5)
- Epitope distribution
- Conservation
- HLA coverage
- Functional domains
- Synthesizeability
Hepatitis: immunopeptidomics for the selection of best SLPs can be done on? (3)
- Antigen loaded DC
- Diseased hepatocytes
- HBV expressing HCC cell-line
What is the basic SLP discovery pipeline?
- Identify target proteins
- Identify conserved regions
- Predict whether these conserved regions contain epitopes that can be presented by DCs
- Design SLP
