Cancer and the�Immune System

A Look Ahead

• Tumors and Metastasis
• Oncogenes and Cancer Induction
• Tumor Antigens
• Tumors and the Immune Response
• Immunotherapy

Cancer and the�Immune System

Cancer

“altered self-cells that have escaped normal growth regulation mechanisms”

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neoplasm: tumor

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benign vs. malignant

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metastasis: spreading of cancerous cells via blood or lymph to various tissues

Metastasis

22.1

Types of Cancers

carcinoma: endodermal/ectodermal tissue

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leukemia/lymphoma: hematopoeitic stem cells

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sarcoma: mesodermal connective tissues

What makes cancer “cancer”?

1. decreased requirements for growth factors and serum
2. are no longer anchorage dependent
3. grow independently of density

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normal cells:

eventually enter G_o

confluent monolayer CHECKPOINT FAILURE

contact inhibition

Malignant Transformation

• are like in vitro cancers
• two phases
1. initiation (changes in genome)
2. promotion (proliferation)

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Malignant Transformation

• chemical and physical carcinogens

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• virally induced transformation

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• cultured tumors: good models for study

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• cancer cells are basically immortal

Oncogenes…

oncogene: “cancer gene”; often found in viral genomes

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proto-oncogene: cellular counterpart which can be turned into an oncogene

What can go right?

• induction of cellular proliferation
• inhibition of cellular proliferation, a.k.a. tumor-suppressor genes
• regulation of programmed cell death

What can go wrong?

• chromosomal translocations
• tandem repeats: HSRs
• mutations in proto-oncogenes
• viral integration
• growth factors and their receptors

Induction of Cancer

Fig. 22.2

Induction of Cancer

Lets Visualize!

• http://science.education.nih.gov/supplements/nih1/cancer/activities/activity2_animations.htm

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Tumors of the Immune System

• Lymphomas
• Solid tumors w/in lymphoid tissue (bone marrow, lymph nodes, thymus)
• Hodgkin’s & non-Hodgkin’s
• http://www.lymphomainfo.net/
• Leukemias
• Proliferate as single cells
• Acute or Chronic depending on the progression of disease
• Acute- appear suddenly and progress rapidly; arise is less mature cells (ie ALL, AML)
• Chronic- much less aggressive and develop slowly; mature cells (ie CLL and CML)

Tumor Antigens�

• TSTAs
• Tumor Specific Transplantation Antigen
• TATAs
• Tumor Associated Transplantation Antigen

TSTAs

• Unique to tumor cells
• DO NOT occur on normal cells in the body
• Novel proteins created my mutation presented on class I MHC
• Can either be chemically/physically induced or virally induced tumor antigens

Chemically/Physically Induced�

Fig 22.7

• Specific Immunologic Response that can

Protect against later challenge by live cells

Of the same line but not other tumor-line

Cells.

• Methylcholanthrene / UV light

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Virally Induced

• Express tumor antigens shared by all tumors induced by the same virus
• Burkitt’s Lymphoma
• Epstein Barr
• HPV

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Fig 22.9

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TATAs

• NOT unique to tumor cells
• DO occur on normal cells in the body
• So where’s the problem?
• Fetal/adult presence
• Concentration of Growth Factors and Growth Factor Receptors

TATAs cont’d

• Oncofetal Tumor Antigens (AFP & CEA)
• Normally appear in fetus before immunocompetence
• Later recognized as non-self
• Oncogene Proteins
• Human Melanomas

Virally Induced Tumors

• Virally induced tumors have the same antigens for each tumor caused by that virus.
• HPV

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Immune Response to Tumors

• Mostly a cell-mediated response
• NK Cells
• Not MHC restricted
• Fc receptor binds to antibody coated tumor cell 🡪 ADCC
• Chedieak-Higashi syndrome
• Macrophages
• Not MHC restricted
• Elicits ADCC
• TNF-alpha
• Immune Surveillance Theory

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So, you have a tumor cell.�Now what?

• You need three things:
1. “See” the cancer
• Ternary complex and costimulation by B7
2. Activate lymphocytes
• Release IL-2, IFN-gamma, and TNF-alpha
3. Cancer cells must be susceptible to killing
• CTL lysis, macrophages, NK cells

Info From:

http://www.brown.edu/Courses/Bio_160/Projects1999/cancer/imevstca.html#Introduction

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But if the body has all these defenses, why do so many people still have cancer?

Conniving Cancer.

• Bad antibodies?
• Some antibodies do not protect against tumor growth, but also ENHANCE it.
• Release of immunosuppressive cytokines
• transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10) and vascular endothelial growth factor (VEGF)
• Hide and go Seeking Antigen
• Antigens actually seem to “hide” in the presence of antibody
• Also, some cancer cells completely shed themselves of the antigen

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Source: Chouaib et al 1997

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Conniving Cancer cont.

• Reduction in Class I MHC Molecules

And the final blow…

• Lack of Co- Stimulatory Signal

Cancer Immunotherapy

• Manipulation of Co-Stimulatory Signal
• Enhancement of APC Activity
• Cytokine Therapy
• Monoclonal Antibodies
• Cancer Vaccines

Manipulation of Co-Stimulatory Signal

• Tumor immunity can be enhanced by providing the co-stimulatory signal necessary for activation of CTL precursors (CTL-Ps)

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• Fig. 22.11a

Manipulation of Co-Stimulatory Signal Cont.

• Basis for Vaccine
• Prevent metastasis after surgical removal or primary melanoma in human patients

Enhancement of APC Activity

• GM-CSF (Granulocyte-macrophage colony-stimulating factor)

remember: CSFs are cytokines that induce the formation of distinct hematopoietic cell lines

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• Fig 22.11b

Cytokine Therapy

• Use of recombinant cytokines (singly or in combination) to augment an immune response against cancer
• Via isolation and cloning of various cytokine genes such as:
• IFN-α, β, and γ
• Interleukin 1, 2, 4, 5, and 12
• GM-CSF and Tumor necrosis factor (TNF)

Cytokine Therapy Cont.

I. Interferons

• Most clinical trials involve IFN-α

• Has been shown to induce tumor regression in

hematologic malignancies i.e. leukemias,

lymphomas, melanomas and breast cancer

• All types of IFN increase MHC I expression

• IFN-γ also has also been shown to increase MHC

II expressionon macrophages and increase

activity of Tc cells, macrophages, and NKs

Cytokine Therapy Cont.

2. Tumor Necrosis Factors

• Kills some tumor cells

• Reduces proliferation of tumor cells without

affecting normal cells

How?

• Hemorrhagic necrosis and regression, inhibits

tumor induced vascularization (angio-genesis)

by damaging vascular endothelium

Cytokine Therapy Cont.

3. In Vitro-Activited LAK & TIL cells

A. Lymphocytes are activated against tumor

antigens in vitro

• Cultured with x-irradiated tumor cells in

presence of IL-2

• Generated lymphokine activated killer

cells (LAKs), which kill tumor cells

without affecting normal cells

In Vitro-Activated LAK and TIF cells Cont.

B. Tumors contain lymphocytes that have

infiltrated tumor and act in anti-tumor

response

• via biopsy, obtained cells and

expanded population in vitro with

• generated tumor-infiltrating lympho-

cytes (TILs)

Monoclonal Antibodies

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• Anti-idiotype

• Growth Factors

-HER2

• Immunotoxins

Cancer Vaccines

• Genetic

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• Biochemical

HPV

Human Papilloma Virus

• E6
• E7

From Normal to Abnormal:

For more info

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• HPV
• Cancer Vaccines

This Day Has Been Brought to you By the Letter…

C

C is for Cancer!