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Designing CD8+ T cell vaccines: It`s not rocket science (yet)

Designing CD8+ T cell vaccines: It`s not rocket science (yet). Jonathan W Yewdell Current Opinion in Immunology 2010. ... But the review is. Therapeutic cervical cancer vaccination. CD8+ vaccines. Function of CD8+ T cells: clearance of viral infections tumor immunity

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Designing CD8+ T cell vaccines: It`s not rocket science (yet)

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  1. Designing CD8+ T cell vaccines: It`s not rocket science (yet) Jonathan W Yewdell Current Opinion in Immunology 2010 ... But the review is ....

  2. Therapeutic cervical cancer vaccination CD8+ vaccines • Function of CD8+ T cells: • clearance of viral infections • tumor immunity • BUT tumors have good Immune-Escape strategies 13 diff. HPV peptides + Freud`s adjuvants CD8+ response HPV induced cervical tumor Yewdell et al., Nat Rev Imm, 2003 Data from: Welters et al., Clin Cacer Res. 2008; Kenter et al., N Engl J Med., 2009

  3. Cross-presentation APC MHC I CD8+ T cell e.g. dying cells, proteins, peptides Aim: Induction of tumor-specific Tmem for therapeutic cancer vaccination Activation of CD8+ T cells Extracellular antigen Intracellular antigen APC APC MHC I MHC II CD4+ T cell CD8+ T cell e.g. viruses e.g. bacteria

  4. Cross-Presentation MHC I Phagosome - to cytosol - pathway endolysosome Vacuolar pathway Cat S MHC I TAP ER Proteasome

  5. 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? Vaccine Strategies Mouse models BUT mice are still not human

  6. How can we learn from cross-priming? • (2) APC modification loss of cross-priming via: • CD8-/CD103- DCs • injection of proapopt. CytochromeC • DC preactivation • (3) Drug modulation of antigen processing • Bortezomib inhibits Proteasome • Chloroquine enhances cytosolic delivery CD8 CD103 Endolysosome (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

  7. gp96 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 work • Immnunogenicity highly dependant on cargo • e.g adjuvant effect of secreted gp96 High immunogenicity Yewdell et al., Nat Rev Imm, 2003

  8. 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 viagap 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 Antigen acquisition in cross-priming

  9. 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?)

  10. 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 TLR-activating substances in the same particle

  11. Thank you for your attention! Questions??? Conclusion Still a lot to do in science before we really understand cross-priming based vaccine strategies

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