Dendritic Cell and its Role in
Adaptive Immunity and Cancer
Immunotherapy
Amna Muhammad
Ph. D scholar
Biochemistry
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Contents
• Introduction
• Dentritic cell and control of immunity
• Immunity
• Antigen Presentation to T cells
• Dendritic Cell and Immune Tolerance
• Dendritic cells and cancer
• Summary
• References
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Introduction
• Immunology has long been focused:
• Antigen
is any substance that causes your
immune system to produce antibodies against
it
• Lymphocytes
are responsible for immune
responses. There are two main types of B cells
and T cells
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• But the mere presence of these two parties does not
always lead to immunity.
• A third party is required
• Dendritic cell (DC) system
- Initiator and modulator of the immune
response
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• How does the immune system respond
to different infections?
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Types of immunity
• Adaptive immunity
• Innate immunity
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Adaptive Immunity
• The adaptive immune or specific immune
response consists of antibody responses and
cell-mediated responses.
• Both responses are carried out by
– B cells
– T cells
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T cells
• Two main types:
1. CD4+: Stimulate other immune cells.
2. CD8+ Cytotoxic T cells: Kill intracellularly-infected
cells.
• Two major types of CD4+ T cells:
1. TH1: Inflammatory T cells -- Stimulate
macrophages and promote inflammatory
responses.
2. TH2: Helper T cells -- Stimulate B-cells to produce
antibodies.
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Antigen Presentation to T cells
• Antigens are presented to T cells as short peptide
fragments bound to (MHC) molecules.
• Two types of MHC in humans and mice:
– MHC I: presents an 8-10 amino acid peptide to CD8+ T cells.
– MHC II: presents a longer peptide (13 aa or more) to CD4+
T cells.
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MHC / T cell Interactions
target cell
Class I MHC
CD8
CD8+ T cell
Class II MHC
Antigen presenting cell
CD4
TCR complex
TCR complex
CD4+ T cell
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CD4+ T cell Activation
• Three signals are required for T cell activation
1. Activation by antigen specific signal
– ( peptide/MHC-TCR binding)
2. Co-stimulatory signal
– CD28/CD80
3. Polarization signal
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CD8+ T cell Activation
• Activation by displaying MHC I/peptide
• co-stimulation
• Activation of the CD8+ cell causes up-regulation of the
IL-2 receptor and production of IL-2, leading to growth
and proliferation.
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Introduction to Dendritic cell (DC)
system
• Professional antigen presenting cells
• Regulation of adaptive immune response
• Tolerize T cells to self-antigens
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Dendritic Cells and Control of
Immunity
o Control B and T cell function
 Capturing antigen
 Antigen processing
 Expression of antigen co-stimulatory molecules
 Migration to lymphoid organ
 Secretion of cytokines
 Activation of lymphocytes
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Capturing Antigen
• Phagocytosis
• Macropinocytosis
• Receptor mediated adsorptive endocytosis
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Antigen Processing
• Antigen is fully digested into amino acids
• Loaded onto MHC class II molecules
• Antigen MHCII complexes are send to cell
surface
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Antigen Processing
Display of MHC II + peptide
on cell surface
Ingestion of microbe
Vesicle fusion,
assembly of
peptide/MHC II
Vesicle carrying
MHC II
Degradtion in
lysozome
MHC II is assembled in ER
Endoplasmic reticulum
Nucleus
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Maturation of DC
Immature DC
Mature DC
High intracellular MHC II
High surface MHC II
Many antigen capturing
receptors
Very less antigen capturing
receptors
Weak T cell stimulator
Powerful T cell stimulator
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Migration of Dendritic Cells
• Loss of adhesion
• Travelling to lymphoid tissues
• Induce T cell response
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Dendritic Cell and Immune
Tolerance
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Immune Tolerence
• Immune system important task is to
- identify what is foreign and what is self
• Failure results in an autoimmune disease
• Diabetes mellitus type 1 or multiple sclerosis
etc
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Thymic Selection
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DC and Cancer
• Constitutive activation of STAT 3 pathway leads to tumor expression
and suppression of dentritic cells
• Commensurate with their roles in regulating cytokine-dependent
inflammation and immunity, signal transducer and activator of
transcription (STAT) proteins are central in determining whether
immune responses in the tumour microenvironment promote or
inhibit cancer.
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Dentritic Cells and Vaccine
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Cont…
• Until recently, most DC vaccines comprised DC or
monocyte precursors of DC, isolated from the patient,
loaded ex vivo with tumour antigen (Ag), and
readministered to the patient. DC that migrated from
the injection site to the draining lymph nodes were
expected to prime or boost memory, tumour-specific T
cells capable of eradicating the tumour.
• To date, the majority of trials have been Phase I studies
on small cohorts of advanced cancer patients who had
failed to respond to conventional therapies
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Cont…
• These trials revealed that this approach:
(1) is feasible in many malignancies;
(2) is well tolerated with minimal toxicity; and
(3) can induce tumour-specific immune responses in many
patients.
• Whilst early DC therapies resulted in limited clinical
benefits, recent advances in our understanding of DC
biology and new knowledge obtained from clinical trials
have identified new strategies that are expected to improve
clinical outcomes. Harnessing the unique capacity of
different DC subtypes to drive specific immune responses in
combinations with approaches designed to overcome
tumour-mediated immune suppression and immune
regulation, are emerging as key strategies for the
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development of new generation DC vaccines.
DC pattern recognition receptors for
cancer immunotherapy
• DC subsets express a range of unique and shared
pattern recognition receptors (PRR), including
CLRs and TLRs that can be harnessed to enhance
the efficacy of cancer immunotherapy.
• Monoclonal antibodies (mAbs) specific for CLRs
can be used to target Ag directly to particular DC
subset(s) in vivo. This attractive approach
circumvents the issues of poor DC migration.
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Summary
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Key Notes
• NF-κB (nuclear factor kappa-light-chainenhancer of activated B cells)
• MHC (major histocompatibilty complex)
• INF (interferon)
• IL (interleukin)
• CD4 ( cluster of differentiation 4)
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References
• Steinman, R. M. and J. Banchereau. 2007. Taking dentritic
cells into medicine. Nature. 449: 419-425
• Banchereau, J. and R. M. Steinman (1998). Dentritic cells
and the control of immunity. Nature. 392: 245-252
• Yu, H., D. Pardoll and R. Jove .2009. STATs in cancer
inflammation and immunity: a leading role for STAT3.
Nature Reviews Cancer. 9: 798-809
• Oriss, B. Timothy , Krishnamoorthy, N. Ray, P. Ray,
Anuradha. 2014. Dendritic cell c-kit signaling and
adaptive immunity: implications for the upper airways.
Current Opinion in Allergy & Clinical Immunology. 14:7-5
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