Designing CD8+ T cell vaccines:
It`s not rocket science (yet)
Jonathan W Yewdell
Current Opinion in Immunology 2010
CD8+ vaccines
Therapeutic cervical cancer vaccination
Function of CD8+ T cells:
13 diff. HPV peptides
+ Freud`s adjuvants
- clearance of viral infections
- tumor immunity
BUT tumors have good ImmuneEscape strategies
CD8+ response
HPV induced
cervical tumor
Yewdell et al., Nat Rev Imm, 2003
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Data from: Welters et al., Clin Cacer Res. 2008; Kenter et al., N Engl J Med., 2009
Activation of CD8+ T cells
Aim: Induction of tumor-specific Tmem for therapeutic cancer vaccination
Extracellular
antigen
Cross-presentation
APC
APC
Intracellular antigen
APC
MHC
MHC II
I
MHC I
CD4+
cell
CD8+
TT
cell
e.g. bacteria
e.g. dying cells, proteins, peptides
CD8+ T cell
e.g. viruses
Cross-Presentation
MHC I
Phagosome - to
cytosol - pathway
endolysosome
Vacuolar
pathway
Cat S
MHC I
TAP
ER
Proteasome
Vaccine Strategies
What is the desired response?
-What peptides?
- response should be as minimal as possible to avoid side-effects and induction
of tolerance
- What Types of CD8+ T cells?
- What anatomic locations should be focused of the response?
How should this response be generated?
- What immunogens should be used
- What dose and
- Which route?
- How many boosts?
Mouse models
BUT mice are still not human
How can we learn from cross-priming?
(2) APC modification
(3) Drug modulation of
antigen processing
loss of cross-priming
via:
CD8
CD103
- Bortezomib inhibits
Proteasome
- Chloroquine enhances
cytosolic delivery
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- CD8-/CD103- DCs
Endolysosome
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- injection of proapopt.
CytochromeC
- DC preactivation
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be nöt ig t.
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be nöt ig t.
(4) Genetic
modulation of antigen
processing
- KO of endosomal
protease IRAP
(1) MHC I Trafficking
- mod. Cytoplasmic domain no
travelling to endolysosome
Yewdell et al., Nat Rev Imm, 2003
Antigen for cross-priming:
Proteins vs. peptides
- Proteins favoured
- antigen stability important
- peptides have to metabolically stable
(law of mass action)
-BUT: chaperoned pepetides might
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gp96
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be
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work
High immunogenicity
- Immnunogenicity highly dependant
on cargo
- e.g adjuvant effect of secreted gp96
Yewdell et al., Nat Rev Imm, 2003
Antigen acquisition in cross-priming
- Cell-delivered antigens
- Nibbling from alive cells
- Phagocytosis of dead cells
- Trogocytosis / „cross-dressing“
-Acquire preformed C1PCs from other APCs during cellular interactions
(e.g. from monocytes which phagocytosed dead cell antigens)
- even TCRs can be exchanges between naive T cells and CD8+ T cells
- Peptide transfer via gap junctions (but more in direct priming)
- Expression of cell death signals enhances cross-presenation
- CLEC9A a necrotic cell detector
- selectively expressed by CD8+ and plasmacytoid DCs
Who is priming?
- Cross-priming appears to be dependant on CD8+ CD103+ DCs
- CD8 features: optimizing endolysosome pH, CLEC9A regulated cross-priming
- CD103+ DCs: migrating subset, transport antigen from periphery to LN
- But in humans?
- maybe BDCA3+ DC similar to CD8+ DC in mouse
-pAPC „Wannabes“ capable of cross-priming:
-pDCs, IFN producing killer DCs, neutrophils (but not in significant quantities?)
Some “practical advice”
- Cross-priming is optimized by expressing long-lived antiges
- extended peptide have increased immunogenicity because of resistance to
protease destruction
- advances in material science offer great promise for polypeptide-based
vaccines: Immunigenicity is increased when delivering antigen and TLRactivating substances in the same particle
Conclusion
Still a lot to do in science before we really understand
cross-priming
vaccineattention!
strategies
Thank
youbased
for your
Questions ???