Huggins Lectureship The Immune System and Cancer A Civil War

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Huggins LectureshipThe Immune System and
CancerA Civil War

• Saturdays
• January 12-March 1, 2008
• Judy Cannon Ph.D.
• Postdoctoral Fellow
• Department of Medicine, Section of Pulmonary and
  Critical Care Medicine

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Quiz-from Week 1 lecture

• What are pathogens?
• Microorganisms that cause disease
• Viruses and fungi
• All bacteria
• What are two key players in the immune response?
• Red blood cells
• B and T cells
• Islet cells
• Cancer cells
• (A) Grow without normal control
• (B) Metastasize
• (C) Mutate DNA
• (D) All the above
• Immunotherapy is
• (A) Non specific cancer cell killing
• (B) Chemotherapy
• (C) Using the immune system to target and kill
  cancer cells

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January 19th 2008Huggins Lecture
2Inflammation and the start of the adaptive
immune response
How does the immune system know when to go?
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Site of infection
Lymph Node
Tumor site
3. T cell recognition Self vs. non-self

• Danger
• Inflammation

2. Presentation of viral products Antigen
presentation
7. Target cell killing
Tumor cell
Virally infected cell
4. Lymphocyte expansion
6. Target recognition
Non-specific cell
Specific T cell
5. Lymphocyte trafficking Getting back to the
right location
Dendritic cell
Specific B cell
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Site of infection
Lymph Node
Tumor site

• Danger
• Inflammation

Tumor cell
Virally infected cell
Virally infected cell
Dendritic cell
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What is inflammation?

• Rubor redness-increased blood flow to site of
  infection
• Calor heat-increased blood flow and cellular
  buildup.
• Tumor swelling-increased cellular buildup at
  site of infection
• Dolor pain-chemical mediators that signal pain
  to brain

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Mediators of inflammationInnate ImmunityFirst
responders
www.lib.mcg.edu/edu/esimmuno/ch1/physresp.htm
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Inflammation Maintaining balance

• Biological systems Need to be in balance.
• Too little leads to pathology.
• Too much leads to pathology.

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Inflammation

• How is it good?
• Leads to the start of the immune response
• How is it bad?
• Causes discomfort!
• Cancer

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What can cause too much inflammation?

• Chronic infections
• Hepatitis B and C-liver
• Helicobacter pylori-stomach ulcers
• Human Papilloma Virus-cervix
• Genetic diseases
• Inflammatory Bowel Disease

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Chronic inflammation and cancer

• Chronic infections
• Hepatitis B and C
• 20-30 times higher risk for liver cancer
• Ulcers caused by bacteria
• 3 times higher risk for stomach cancer
• Human Papilloma Virus
• Causes over 70 of all cases of cervical cancer
• Genetic diseases
• Inflammatory Bowel Disease
• 2-3 times higher risk for colon cancer

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How does inflammation cause cancer?

• Not clear
• Studies show that some of the mediators of
  inflammation might cause DNA damage.

Treatments?

• Some evidence that anti-inflammatory drugs such
  as aspirin might decrease cancer rates.

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When is inflammation good?

• Kicks off immune response.
• Signals from pathogens that tell the immune
  system that we are infected with a pathogen.

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Coleys toxin

• Dr. William Coley
• Injected cancer patients with bacteria
• Saw dramatic regression or complete cure in a few
  patients
• Induce inflammation?

Courtesy Nature Publishing Group
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Mediators of inflammationInnate ImmunityRapid
Response Team Macrophages and Neutrophils
www.lib.mcg.edu/edu/esimmuno/ch1/physresp.htm
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Danger signals
www.biology.ualberta.ca/.../fly_lab/fly_lab.htm
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Drosophila Melanogaster

• One of the most intensively studied genetic
  organisms
• Classical genetic studies throughout 20th century
• Toll receptors identified in 1988.
• Important for fruit fly immunity to fungus

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Humans (and all mammals) have Toll-like
receptors, or TLRs
www.itb.cnr.it/
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TLRs signal danger to the immune system for
bacteria and viruses
Bacterial and viral components
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Site of infection

• Danger
• Inflammation

2. Presentation of pathogenic products Antigen
presentation
Virally infected cell
Dendritic cell
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Dendritic cells

• Reconaissance team
• Gather information to take to the specialists-
• army T cells
• air force B cells
• Dendritic cells start eating up nearby cells
• Dendritic cells chew up cellular material and
  then display them to B and T cells
• Dendritic cells move to lymph nodes

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Dendritic cells-bridging the local and the lymph
node response
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Figure 1-7
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Site of infection
Tumor site
Lymph Node
1. Inflammation
2. Antigen presentation
Tumor cell
Virally infected cell
Dendritic cell
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Infectious Agents vs. Cancer

• External bacteria or virus

• Internal cell from self

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Site of infection
Tumor site
Lymph Node
1. Inflammation
2. Antigen presentation
Tumor cell
Virally infected cell
Dendritic cell
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An intelligence failure What happens if there
is no inflammation?

• No activation of local inflammatory response
• No activation of dendritic cells and adaptive
  immune response
• No antigen presentation-no T or B cell activation

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Imiquimod or Aldara

• FDA approved, on market now
• Used to treat superficial basal cell carcinoma
• Annual sales exceeded US 100 million
• TLR agonist binds and activates Toll-Like
  receptor
• Induces local inflammatory response

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Imiquimod-brings first responders
www.lib.mcg.edu/edu/esimmuno/ch1/physresp.htm
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Efficacy of Imiquimod

• In clinical trials, between 70-100 of patients
  responded with complete clearance of basal cell
  carcinoma.
• Side effect edema, burning sensation

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Site of infection
Lymph Node
Tumor site
1. Inflammation
2. Antigen presentation
Tumor cell
Virally infected cell
Dendritic cell
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Key points Lecture 2

• Chronic inflammation can cause cancers.
• Inflammation is a necessary first step to the
  immune response to bring first responders to
  control the infection
• Inflammation leads to activation of antigen
  presentation and migration of dendritic cells to
  lymph nodes
• Activating inflammatory responses can lead to
  clearance of certain types of tumors

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Next week Lecture 3Immune cell recognition
January 26th 2008

• How does the immune system see pathogens or
  cancer cells?
• Immune cell recognition, autoimmunity, and cancer
  antigens.