Cancer and the Immune System

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Cancer and theImmune System

• Amar Bhatt
• Shirley Masand
• Jaime Warmkessel

Immunology Chapter 22 April 22, 2003
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A Look Ahead

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

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Cancer and theImmune System
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Cancer

• altered self-cells that have escaped normal
  growth regulation mechanisms
• neoplasm tumor
• benign vs. malignant
• metastasis spreading of cancerous cells via
  blood or lymph to various tissues

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Metastasis
22.1
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Types of Cancers

• carcinoma endodermal/ectodermal tissue
• leukemia/lymphoma hematopoeitic stem cells
• sarcoma mesodermal connective tissues

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What makes cancer cancer?

• decreased requirements for growth factors and
  serum
• are no longer anchorage dependent
• grow independently of density
• normal cells
• eventually enter Go
• confluent monolayer CHECKPOINT FAILURE
• contact inhibition

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Malignant Transformation

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

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Malignant Transformation

• chemical and physical carcinogens
• virally induced transformation
• cultured tumors good models for study
• cancer cells are basically immortal

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Oncogenes

• oncogene cancer gene often found in viral
  genomes
• proto-oncogene cellular counterpart which can
  be turned into an oncogene

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What can go right?

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

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What can go wrong?

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

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Induction of Cancer
Fig. 22.2
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Induction of Cancer
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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)
• Hodgkins non-Hodgkins
• 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)

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Tumor Antigens

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

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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

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Chemically/Physically Induced

• 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

Fig 22.7
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Virally Induced

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

Fig 22.9
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TATAs

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

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TATAs contd

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

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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
• See the cancer
• Ternary complex and costimulation by B7
• Activate lymphocytes
• Release IL-2, IFN-gamma, and TNF-alpha
• Cancer cells must be susceptible to killing
• CTL lysis, macrophages, NK cells

Info From http//www.brown.edu/Courses/Bio_160/Pr
ojects1999/cancer/imevstca.htmlIntroduction
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But if the body has all these defenses, why do so
many people still have cancer?
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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

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And the final blow

• Lack of Co- Stimulatory Signal

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Can you tell me how to get...
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...How to get to Therapy Street?
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Cancer Immunotherapy

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

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Manipulation of Co-Stimulatory Signal

• Tumor immunity can be enhanced by providing the
  co-stimulatory signal necessary for activation of
  CTL precursors (CTL-Ps)
• Fig. 22.11a

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Manipulation of Co-Stimulatory Signal Cont.

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

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Enhancement of APC Activity

• GM-CSF (Granulocyte-macrophage colony-stimulating
  factor)
• remember CSFs are cytokines that induce the
  formation of distinct hematopoietic cell lines
• Fig 22.11b

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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-a, ß, and ?
• Interleukin 1, 2, 4, 5, and 12
• GM-CSF and Tumor necrosis factor (TNF)

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Cytokine Therapy Cont.

• I. Interferons
• Most clinical trials involve IFN-a
• 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-? also has also been shown to increase
  MHC
• II expressionon macrophages and
  increase
• activity of Tc cells, macrophages, and NKs

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Cytokine Therapy Cont.

• 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

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Cytokine Therapy Cont.

• 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

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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)

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Monoclonal Antibodies

• Anti-idiotype
• Growth Factors
• -HER2
• Immunotoxins

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Cancer Vaccines

• Genetic
• Biochemical

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HPV

• Human Papilloma Virus
• E6
• E7

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From Normal to Abnormal
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For more info

• HPV
• Cancer Vaccines

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This Day Has Been Brought to you By the Letter

• C
• C is for Cancer!