Cancer and the Immune System_BS963_EK

7/29/2019 Cancer and the Immune System_BS963_EK

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Cancer and the immune system

BS963

Elena Klenova, e-mail:[email protected]


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Immunobiology : the immune system in health and disease

/Charles A. Janeway, Paul Travers, Mark Walport and Mark Shlomchik; 2005,

Garland Science Publishing

Janeway's immunobiology 7th ed. / Kenneth Murphy, Paul Travers, Mark

Walport ; with contributions by Michael Ehrenstein ... [et al.]; 2009, Garland

Science Publishing

The Immune system/Peter Parham, 2005, Garland Science Publishing

Cellular and molecular immunology / Abul K. Abbas, Andrew H. Lichtman,Shiv Pillai/ 2007, Philadelphia : Saunders Elsevier ( also the 2005 Edition)

Dunn GP, Koebel CM, Schreiber RD: Interferons, immunity and

cancer immunoediting.Nature Reviews Immunology 2006, 6:836-848.

Ichim, C.V. Revisiting immunosurveillance and immunostimulation:

Implications for cancer immunotherapy J Transl Med 3, 8 (2005). Pardoll D. Does the immune system see tumors as foreign or self? Annu. Rev.

Immunol. 2003, 21:807-39

Smyth, M. J. et al. A fresh look at tumor immunosurveillance and

immunotherapy. Nature Immunology 2001, 2: 293 299.

Recommended reading


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Plan of the seminar

1. General Introduction ( Cancer and Immune system).2. Theories of the role of the immune system in cancer.

3. Cells of the immune system involved in anti-tumour

response and basic mechanisms of anti-tumourimmunity.

4. Tumours antigens: novel or over-expressed proteins

produced by tumours that may be recognized by the

immune system.

5. How do tumour cells escape from the immune

system?

6. Anti-tumour therapy. Anti-tumour vaccines.


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1. General Introduction ( Cancer

and Immune system).


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Cancer

Uncontrolled growth produces a tumour

( neoplasm).

Benign - a tumour that is not capable of

indefinite growth. It does not kill the host.

Malignant - a tumour that grows

indefinitely and often spreads (metastasis).

It can kill the host.


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Types of Cancer

(based on the type of affected tissue)

Carcinoma: Cancer of endo or ectoderm e.g.

Skin or epithelial lining of organs.

Sarcomas: Cancer of mesoderm e.g. bone.

Leukemias and Lymphomas: Cancers of

hematopoietic cells


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The Immune System

Innate (non-specific) immune

system (Granulocytes, Macrophages)

immediately available for combat

Adaptive (specific) immune system(T and B-Lymphocytes)

Production of antibody (Ab) or cells

specific to combat a particular antigen


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Innate and adaptive responses work together

Innate

Antigen independent

Immediate (hours)

Neutrophils

NK (Natural Killer) cells

Macrophages

Adaptive

Antigen-dependentSlower (days)

T cells

B cells

Dendritic cells a link between the innate and adaptive systems!

Innate immune responses help form adaptive immune

responses, and

Adaptive immune responses utilize the machinery of innate

immunity for effector function


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Evidence for the role of immune system in

tumor rejection

Spontaneous regression Regression of metastases after removal of

primary tumor

Regression after chemotherapy

Infiltration of tumors by lymphocytes andmacrophages

Lymphocyte proliferation in draining lymph

nodes

Higher incidence of cancer afterimmunosuppression/immunodeficiency (AIDS,

neonates, aged, transplant patients)


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Tumour rejection antigens are specific for

individual tumours


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2. Theories of the role of the

immune system in cancer.


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Two distinct theories of the role

of the immune system in cancer

Immunosurveillance - the tumour-

suppressing role of the immune system.

Immunostimulation - the tumour-

promoting role of the immune system.

Tumour and immune system interact:

mutual influence!


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Immunosurveillance (immune

surveillance ) As early as 1909 Paul Ehrlich postulated that

cancer occurs spontaneously in vivo and that the

immune system is able to both recognize and protect

against it . In the late 1950s Lewis Thomas introduced the theory

of immunosurveillance, which was subsequently

developed by Sir MacFarlane Burnet .

The theory states that immunosurveillance is aphysiologic function of the immune system. Cancerous

cells seen as foreign and thus can be constantly

eliminated by immune surveillance.Ichim, C.V. J Transl Med3, 8 (2005).


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Cancer immunosurveilance: evidence in humans

Increased incidence of virally-induced tumours in

Immunosuppressed patients

Studies showing increase in de novo malignant

melanoma in organs transplant patients

25-fold increase in incidence of lung

carcinoma in cardiac transplant patients

Reverse correlations between tumour infiltrating

lymphocytes and tumour survival

Dunn et al. Nature Reviews Immunology6, 836

848(2006)

l d


15/44Dunn et al. Nature Reviews Immunology6, 836848 (2006)

Cancer immunosurveilance: evidence in mice


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Immunostimulation (immune stimulation)

The proof of the principle that an inappropriate type of

immune response will enhance tumour growth wasdemonstrated as early as 1907 by Flexner and Jobling,

who showed that injection of dead autologous tumour

cells enhanced the growth of pre-existing tumours.

In 1972, Richmond Prehn formulated the theory of

immunostimulation of tumour growth. This theory states

that, in contrast to the strong immune responsegenerated by transplantable tumours, a quantitatively

mild immune response, such as that generated by

spontaneous tumors, is stimulatory to the growth of

neoplasia.


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How the conflicting roles of the immune

response in neoplasia can be explained?

Modern view: The immune system is not a singleentity, but a complex system of constituents. The

concept of immunosurveillance has been modified

and is now considered in three phases:1. Elimination phase - recognition and

destruction of the tumour cells

2. Equilibrium phase occurs if elimination is

not successful. Tumour cells undergo changes in

a process called immunoediting.

3. Escape phase- tumour cells evolved enough

to grow unimpeded and form a tumour


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3. Cells of the immune systeminvolved in anti-tumour response

and basic mechanisms of anti-

tumour immunity.


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The immune system provides one of the body's main

defenses against cancer.

When normal cells turn into cancer cells, some of the antigenson their surface change.

These new or altered antigens flag immune defenders,

including cytotoxic T cells, natural killer cells, and macrophages.

Natural

IFN-g

IFN-g


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Immune cells are generated during hematopoiesis

C ll f h i i l d i


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Functions:

Phagocytosis

Antigen presentation to T cells

Phagocytosis of microorganisms and

antigen presentation to T cells

Kill tumor and virus-infected cells

Regulates humoral and

cell-mediated immune responses

Cells of the immune system involved in tumour response


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T-cell classification

Classification is based on the Structure & antigen specificity of TCR (T-cell receptor)

T cells are divided into two major groups: CD4+ T-helper and CD8+ T-cytotoxic cells.

The differentiation of T cells into CD4 vs. CD8 occurs during their development in the thymus.

T cells: CD 4 & 8 Accessory Molecules

CD4 + helper T cells (TH); further subdivided into type 1 and type 2, also known as Th1 and Th2. The

differentiation of Th cells into Th1 and Th2 occurs only after these cells have been activated during

an immune response, in the peripheral lymphoid system.

- Only recognize antigen bound to MHC class II molecule

CD 8 + cytotoxic T cells (TC)

-Only recognize antigen bound to MHC class I molecules

T cells require two signals for activation:

1 -from TCR /MHC-antigen complex & CD4 or CD8/MHC complex

2-from an accessory molecule CD28

When all appropriate signals are received, T-cells clonally expand as a result of IL-2 secretion forming

a population of T-cells with the same antigen specificity----further differentiation into memory

& effector cells

MHC M j Hi t tibilit C l R l f MHC M l l


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Membrane-bound glycoproteins

- Class I and Class II MHC molecules

- MHC genes highly polymorphic-within eachspecies there are many

different forms (alleles)

MHC function as antigen-recognition

molecules

- Can bind to a spectrum of antigenic peptides;polymorphism allows

for diversity in antigen recognition

MHC I ---expressed on all nucleated cells

- Present endogenous antigens

-CD 8 + (Tc cells) -recognize antigen on MHC I

MHC II ---expressed on Antigen presenting

cells (APC)

- Present exogenous antigen

- CD 4 + (Th cells) -recognize antigen on MHC II

MHC-Major Histocompatibility Complex: Role of MHC Molecules


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Anti-tumour immunity: basic

mechanisms

Immunology 7th Ed

( D. Male et al)


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Antigen presenting cells (APC)

Dendritic Cells (DC)

DCs are the interface between innate and adaptiveimmunity

DCs are immature as they circulate waiting toencounter pathogens. At this point, they are highly

phagocytic, but not good stimulators of adaptive T cellresponses

Once they are activated, they secrete cytokines toinitiate inflammation and then they migrate to lymph

nodes and mature As mature DCs they are very efficient APCs for T cell

stimulation

Other APCs: macrophages, neutrophils, B-

lymphocytes, monocytes.


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Anti-tumour immunity: basic mechanisms

Smyth, M. J. et al. Nature Immunology 2, 293 - 299 (2001)

Presence of tumour cells

and tumour antigens may

initiate the release ofdanger signals; cytokines,

heat shock proteins (HSP),

uric acid etc.

Activation and maturation

of dendritic cells, which

present tumour antigens to

CD8 and CD4 cells

Clonal expansion of CD8 and

CD4 T cells; migration fromthe lymph node

Subsequent T cell mediated

destruction of tumour cells


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The cellular basis of tumour immunology: CTL - tumor cell interactions


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Antigen presentation by antigen presenting cells

N t l Kill (NK) C ll


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Natural Killer (NK) Cells- First identified by having the ability to lytically kill certain

tumor cell lines without prior sensitization

- Kill target cell by release of cytotoxic granules containinggranzymes and perforin which penetrate target cellmembrane and induce programmed cell death

- Can mediate Antibody-Dependent Cellular Cytotoxicity(ADCC); (mechanism of immunologic lysis in whichcellular targets sensitized by specific antibodies areefficiently and selectively lysed by nonspecific effectors)

- Kill virally-infected cells with missing MHC class I

- Activated by IFN-a/b or IL-12 (produced rapidly byactivated macrophages)

- Activated NK cells secrete IFNg, acts on macrophages toincrease microbial phagocytosis and killing

Fig 8-3


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Basic facts about NK cells

They get easily activated, do not adapt and kill MHC-negative cells.


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4. Tumours antigens: novel or over-expressed

proteins produced by tumours that may be

recognized by the immune system.


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Major Histocompatability Complex antigens

TSTA

TATA

TSTA: unique to a tumourPlay an important role in tumor rejection.

TATA: shared by normal and tumour cells

Tumour-associated developmental Ag (TADA)

Tumour-associated viral Ag (TAVA)

Tumour-specific

transplantation Ag

Tumour-associated

transplantation Ag

Antigens expressed on tumour cells

Tumor Associated Developmental


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Tumor-Associated Developmental

Antigens

Found on cancer cells and on fetal cells.

Do not trigger anti-tumor immunity.

Used in diagnosis.Alpha-fetoprotein(AFP)

Cancers of liver

Carcinoembryonic Ag (CEA)colorectal cancer

Identification of tumour antigens


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Identification of tumour antigens

Use the immune system as a tool forthe identification of

immunogenic antigens

Gene profiling genomics or transciptomics

Proteomic approaches

peptidomics, serum profiling

In-silico bioinformatic approaches

probing EST databases

O h T i d i


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Other Tumor associated antigensShared tumour antigens: common in different tumours

Cancer-testis antigensMAGE family etc.

Differentiation antigens

Melan-A/MART-1, gp100

Over-expressed proto-oncogenesHER2/neu, WT1

Some additional antigens

MUC-1 (over-expressed)

Unique tumour antigens

Point mutations: p53, Raf, Bcr/Abl

viral antigens: HPV, EBV etc.


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5. How do tumour cells escape

from the immune system?


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Malignant cells can be controlled by

immunosurveillance

NK Natural Killers

CD4, CD8 and gd types of T-lymphocytes


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6. Anti-tumour therapy.

Anti-tumour vaccines.


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Ideal tumour antigen:

- displays tumour-specificexpression

- is immunogenic

- plays an important functional rolein cell survival / differentiation /

metastasis etc.


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Specific

Active Immunization: Vaccination with viral

Antigens: e.g.

Hepatitis B virus

Human Papilloma virus (HPV) success

story.

Ab Therapy

Abs specific for oncogene product e.g. Abs

against HER2/neu (Herceptin ortrastuzumab)

Anti-tumour therapy


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Nonspecific:

BCG (Bacillus Calmette-Guerin) Mycobacteria

used as an adjuvant - melanoma, bladdercarcinoma

Irradiated tumour cells ( with or without BCG)

Normal

Macro

phage

Tumor

Activated

Macro

phage

Tumor

lysis

Ad ti i th


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Adoptive immunotherapyex vivo manipulation and transfer of effector cells

- Antibody-Dependent Cellular Cytotoxicity (ADCC)

Gene therapy

Introduce cytokine genes for IL-2, IL-4, IL-12, IFN-g etc into tumor cells toinduce immune response.

tumour T cell

IL-2

IFN-g

Cancer and the Immune System_BS963_EK

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