Tumor immunology Flashcards
Why is CD4 T cell help important during therapeutic vaccination?
When CD4 T cells interact with DC HLA II in the presence of cytokines and co-stimulation, CD40/CD40L interactions send help signals, upregulating CD70 on the DCs that can interact with CD27 on CD8 T cells along with HLA I. This releases IFNy and IL-12 and increases CD8 potency and longevity. CD8 T cells can then proliferate into target antigen specific effector CD8 T cells that can target diseased cells.
What are the two types of tumor-associated antigens? Explain them.
Overexpressed self antigens (self-explanatory) and cancer germline antigens (antigens from genes that are normally expressed in germ cells and trophoblast tissues but silenced in somatic tissues. They are also aberrantly expressed in cancers)
Why can tumor-associated antigens be good targets for therapeutic vaccination, and why wouldn’t they?
Overexpressed antigens have variable tumor specificity, there is a high level of central tolerance (since they are self antigens), but they are prevalent in many patients.
Cancer germline antigens have good tumor specificity, low central tolerance and are prevalent in many patients.
What are the three types of tumor-specific antigens?
Oncoviral (such as HPV), shared neo-antigens and private neoantigens.
Why are tumor specific antigens good targets for therapeutic vaccination. Which one is less favorable and why?
They are all tumor-specific and there is no central tolerance against them. Oncoviral and shared neo-antigens also prevalent in many patients. Privatre neo-antigens are more specific to patients, and thus require personalized therapy, which is costly and time-consuming.
How long are peptides most optimally recognized by HLA I and HLA II molecules?
HLA I:: 9 aa is ideal, HLA II can recognize longer motifs
What are the different ways neo-epitopes are formed? (4)
- Non-immunogenic point mutations (where the mutation faces away from the TCR)
- Immunogenic point mutations (where an anchor residue is mutated or the amino acid projects toward the TCR)
- Insertions or deletions
- Frameshifts (caused by insertions or deletions that shift the reading frame, leadding to a new stretch of proteins)
Which type or mutation can lead to shared neo-epitopes, and how does that work?
Frameshifts, since mutations at different positions can lead to the same neo-epitopes
What’s the deal with different vaccine antigens and cross-presentation?
DNA and RNA vaccines bypass the need for cross-presentation since the cells can directly produce the peptides and present them on MHC I. Synthetic long peptides are more efficient at cross-presentation than short peptides and whole proteins. Short peptides also can induce tolerance because they can be directly presented on MHC I by non-APCs that do not co-stimulate.
What are the pros of using DNA and RNA vaccines?
They are inherently adjuvants since endosomal TLRs can be activated by DNA and RNA. They also bypass the need for cross-presentation, and DNA vaccines can also co-express chemokines to target specific DC subsets.
What are downsides of short peptides as antigen forms for vaccination?
They are HLA restricted due to their short length, so they can only be presented on HLA I. They can also be expressed by non-APCs, which can not co-stimulate T cells and that can lead to tolerance.
Do peptides induce B cell responses?
There may be some exceptions (such as in the case of linear epitopes), generally no, not effective ones at least. They lack tertiary structures and thus any antibodies produced that target those peptides may not recognize the protein on which the peptide is based.
What is a pro and a con of using whole proteins as antigen forms for vaccines?
Pro: They induce (effective) B cell responses
Con: Cross-presentation is less efficient
What is the main downside of mRNA and DNA vaccines?
Cold chain necessity
What are downsides of using cellular DC-based vaccine platforms? (4)
It requires personalized vaccine preparation since it uses the patient’s own DCs, which is costly and time-consuming. Ex vivo culture is also not optimal for DCs (qualitywise) and it is difficult to purify natural DCs in large numbers. Determining optimal timing and route of administration is also a challenge.
What is passive and active targetting of DC subsets?
Passive: Proteins/SLPs of different lengths and different sites with adjuvants
Active: Proteins, peptides or mRNA particles conjugated to antibodies or ligands to target specific DC or macrophage subsets
What functions can antigen vehicles have? (4)
- Targetted delivery
- Protection
- Biodistribution
- Controlled release
What cancer patients may benefit from therapeutic vaccination before checkpoint inhibition?
Those that do not respond to checkpoint inhibitors (immune desert tumors)
What 3 main techniques are used to assess therapeutic vaccine induced immune responses?
After 10-14 day expansion of PBMCs and moDCs, restimulation with the vaccine antigen and then: IFNy ELISA, IFNy ELISPOT, flow cytometry
How do you test immune responses to SLP pools?
Proliferation with SLP pool, then SLP components 1 by 1 to see which ones induce a response
What are the 3 main steps in producing a personalized SLP or mRNA vaccine against a tumor?
- DNA and RNA seq to identify tumor-specific antigens
- HLA typing
- Prediction of personalized HLA-binding peptides
What can you do if patients progress after therapeutic vaccination? Why not do that in the first place?
Administer checkpoint inhibitors. In HBV, responses are lowered partially since there is a lack of T cell priming. With therapeutic vaccinations, you can boost this response, and then use checkpoint inhibitors to prevent or reverse exhaustion.
What may be better for costs and efficacy than personalized therapeutic vaccinations?
Shared antigen-based vaccines?
What is the problem with T cell responses in chronic HBV?
Low responses do to ineffective T cell priming, and the response that is there is exhausted due to prolonged antigen exposure
What is the goal of DC therapy?
Improve effective priming of T cells
How can DCs be manipulated in- or ex vivo? (4)
- Administration of DC activating factors
- Administration of DC-mobilizing agents
- Administration of antigens and adjuvant (indirectly or directly)
- Adoptive transfer of autologous, antigen-loaded and activated DCs
How is antigen-loading and activation of autologous DCs done for tumor therapy? (5 steps)
- Leukapharesis
- Isolation of monocytes
- Culture into immature DCs
- Pulse with tumor cell lysate
- Inject now activated mature DCs back into patient
What are allogeneic tumor cells used for and is their use effective?
To go around needing tumore lysate from each individual patient, genetically distinct tumor can be used to activate DCs for therapy instead. It is preclinically effective
What can be done to improve DC therapy? (2)
- Targetting tumor-associated macrophages
- Combining with checkpoint inhibitors
What are tumor-associated macrophages?
They have a suppressive phenotype. Higher TAM proportions compared to CD8 T cells is associated with lower survival rates.
How are TAMs inhibitory?
DC maturation suppression
T cell supression
Induction of Tregs
PD-L1 expression
How can TAMs be targetted?
Depletion through CSF1R inhibition
