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Dendritic Cell and its Role in Adaptive Immunity and Cancer Immunotherapy

Amna MuhammadPh. D scholarBiochemistry

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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

Class II MHCClass I MHC

TCR complex

CD8

CD8+ T cell

target cell

CD4

Antigen presenting cell

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

Endoplasmic reticulum

Nucleus

Vesicle carryingMHC II

MHC II is assembled in ER

Display of MHC II + peptideon cell surface

Ingestion of microbe

Degradtion in lysozome

Vesicle fusion, assembly of

peptide/MHC II

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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 development of new generation DC vaccines.

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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-chain-enhancer 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