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Dendritic cells in cancer immunotherapy
Aimin Jiang
Feb. 11, 2014
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Dendritic cells at the interface of innate and adaptive immune
responses
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MHC-II
Dendritic cell
T cell TCR
immunity tolerance
Dendritic cells: initiators of adaptive immune responses
Naive
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DC cancer vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains a small amount of an agent that resembles a microorganism. The agent stimulates the body's immune system to recognize the agent as foreign, destroy it, and "remember" it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters.
It often contains an adjuvant that activate DCs.
Could be preventive (humoral) or therapeutic (celleluar, cancer vaccine)
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Why do we need cancer vaccine?
Immune responses against cancer cells were not strong enough. Immune system can reject tumors!!! Passive Immunotherapy: Transfer of T cells or antibodies ---- no memory T cells Active immunotherapy: DC vaccine ------tumor-specific effector and memory T cells
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Three approaches of DC-based cancer vaccine
Advantage: safe, some clinical responses, potential Dendreon’s Provenge (DCs) was approved for prostate cancer treatment.
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Dendritic Cells as Therapeutic Vaccines: Original Concept
(circa 1992) • Goal: Induce antitumor (or antiviral) immunity using
autologous DC pulsed with tumor Ag • Methods
– Generate DC in vitro from circulating precursors – Load DC with Ag – Return DC to patients
Edgar Engleman
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Dendritic Cell Based Vaccines in Cancer Treatment
Antigen-Pulsed DC Vaccination (systemic)
Leukapheresis DC Generation (GM-CSF, IL-4)
Tumor Antigen
Immune & Clinical Monitoring
Vaccination (Intratumoral)
DC Maturation (TNF, CD40-L)
Ag loading
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Problems with Customized DC Vaccines
• Poor efficacy -- most tumor bearing patients do not respond
• Best tumor Ags, DC activation method, route of delivery all unknown
• Cost and complexity are high
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A New Approach to Vaccination
1. Receptor-mediated antigen targeting to dendritic cells in peripheral lymphoid tissues.
2. Simultaneous maturation of the antigen- capturing dendritic cells.
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MMR DEC-205
DEC-205, a Homologue of the Macrophage Mannose Receptor, with 10 vs 8 External,
Contiguous, C-type Lectin Domains
Jiang et al, Nature 375: 151-155 (1995)
1. Available mAb to DEC-205
2. High expression by lymph node DCs of DEC-205
3. Rapid targeting of mAb to DCs in lymph nodes including distal tissues.
4. Access to MHC class I & II
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DEC-205 on Dendritic Cells in the T Cell Areas of Mouse Lymph Nodes
B B
T
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Draining nodes
αDEC-205 targeting kinetics Subset targeting
Evaluate:
C57BL/6
30 minutes to 3 days
Harvest draining/distal nodes and spleen
Rapid, Efficient and Durable Targeting of αDEC-205 Antibodies to DCs, systemically, in situ
61.6
38.3
49.1
26.7 3.14 0.51 3.61
41.1
29.0
43.6
0.33 19.1
29.5
21.5
28.6
Isotype 30min.
6 hrs. 15 hrs.
3 days
αDEC-205
CD8α
10 µg αDEC-205:Alexa488 or isotype control (s.c.)
Distal nodes Spleen
Enrich for CD11c+
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OVA
250,000 ng
25,000 ng
2,500 ng
Monovalent αDEC-205:OVA
250 ng
50 ng
2 ng
OT-I OT-II
% Max. Count
CFSE
Iso.:OVA
PBS
Control OT-I (CD8+ )
OT-II (CD4+)
Iso.:OVA
PBS
Targeting Dendritic Cells with α-DEC-205:OVA Markedly Enhances Presentation to CD4+ and CD8+
T cells (CFSE-labeled) in vivo in the Steady State
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Day 7 Day 30
0 0.5 1.0 1.5 2.0
αDEC-205:OVA + αCD40
OVA + CFA
Ex vivo pulsed spleen DC
Naïve
0 2.0 4.0 6.0 8.0
Lymph node Spleen
% IFNγ+ CD8+ Lymphocytes
0.75% 3.0%
7.0% 1.3%
A Single Vaccination with α-DEC-205:OVA + α-CD40 Induces CD8+ T Cell Immunity of Greater Magnitude
(and Duration) than Current “Gold Standards”
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Initial tumor area (OVA-B16) 17 19 7 13 11 15 9
0
200
300
400
100
Time After Treatment (days)
OVA + CFA
Ex vivo OVA-pulsed DCs
PBS αCD40
αDEC-205:OVA + αCD40
Tumor area
(mm2)
Vaccination with α-DEC-205:OVA + α-CD40, but not DC-OVA or OVA / CFA,
Exerts a Therapeutic Effect on 7 Day Tumors
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β-catenin activation leads to DC maturation without the production of cytokines β-catenin activation in DCs leads to CD4+ T cell tolerance in models of autoimmune disease.
β-catenin signaling in determining DC function
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Targeted deletion/activation of β-catenin in DCs
Pathway inactivation: β-cat-/- (CD11c-Cre β-catFL/FL )
Pathway activation: β-catactive (CD11c-Cre β-catExon3FL/FL)
Sonja Zahner Bjoern Clausen
Tolerance Immunity
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Whether tumors activate β-catenin in DCs?
β-catenin
WT-T WT
Splenic DCs of tumor-bearing mice
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β-catenin activation and tumor-bearing mice exhibited suppressed CD8 recall responses
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How activation of β-catenin in DCs affects anti-tumor CD8 T cell immunity?
αDEC-OVA (CpG)
Naïve CFSE+ OT1 In vitro restimulation 3, 5, 8 days 3 days
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Tumor-mediated inhibition of cross-priming is β-catenin-dependent.
αDEC-OVA (CpG)
Naïve CFSE+ OT1 In vitro restimulation 3 days 3 days
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Tumor-bearing β-catenin-/- mice exhibited normal CD8 memory responses when
transferred into WT mice
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Blocking β-catenin reversed tumor-induced inhibition of cross-priming
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β-cateninactive DCs exhibited increased FOXO3 expression and reduced NF-kB activation upon
TLR signaling