Tumor Immunology

Question 1

1. What is the Tumor Surveillence Theory?
2. What evidence is there in immunodeficient and immunosurpressed people that contradicts this hypothesis?

Answer 1

1. Adaptive immune response is NOT for for dealing with foreign substances
   
   • Instead it is a way to detect changes to self due to damage or mutation
   • T-cells monitor the surfaces for abnormal. Kill them before they can make a mutant malignant clone
2. Tumors that these people get aggregate in the lymphoid system
   
   • Nude mice with no thymus lack an immune system and SHOULD get tumors easily
   • Instead, tumors rare in the mice. –NK cells not part of traditional immunity but are deadly.

Question 2

What are the 3 stages of cancer immunoediting?

Answer 2

1. Elimination: As cells proliferate, there are inevitably neoplasmic mistakes made
   
   • These neoplasms are usually eliminated immediately via immunoediting
2. Equilibrium: Body can’t/doesn’t kill every single cancer cell it makes, so they stay in hiding
   
   • Like a rebel force in hiding waiting for the right time to start a revolution
   • When host’s immunity falls, mutations can accumulate and lead to reactivation
3. Escape: Tumor cells mount an offensive are a large enough force to inhibit CTL’s
   
   • CTL’s are inhibited by tumor via inhibition checkpoints using CTLA-4 and PD-1

Question 3

How does a Tumor Specific Antigen (TSA) differ from a Tumor Associated Antigen (TAA)?

Answer 3

TSA (Tumor-specific antigen): tumor cell antigens not found on normal cells. Easy to target

TAA (Tumor-associated antigens ): tumor cell antigens found on normal cells but more common or weird looking on tumor cells. Harder for the immune system to target

Question 4

1. What type of tumor antigen’s do Viruses, Mutant genes, and Normal genes make?
2. What has a better prognosis–a tumor with few mutation or a tumor with a lot of mutations?

Answer 4

1. Viruses: usually make TSA
   
   • Mutant Genes normally make TSA
   • Normal Genes normally make TAA (these TAA are often made in excess by tumor cells)
2. A tumor with more mutations usually has a better prognosis because there it presents more varied epitopes for the immune system to potentially recognize it
   
   • A freak that dresses up and acts like a freak is easier to spot, than a serial killer that dresses acts normal.

Question 5

What is a carcinoembryonic antigen (CEA) and what is it useful for?

Answer 5

CEA:Oncofetal antigen found in the blood of patients with colon carcinoma

• Kits for CEA should not be used routinely because of false positives (not used for screening)
• Only use is really if you have a high index of suspicion or when you need to confirm that you excised all of the cancer (make sure you got it all out)

Question 6

As it related to MHC Class I when would you use CTL’s on tumor cells? When would you use NK cells?

Answer 6

If tumor makes lots of Class I? use CTL

If tumor stops making Class I? use NK

Question 7

What is the nature and therapeutic use of a Tumor-infiltrating Lymphocyte (TIL)?

Answer 7

TIL:

• Cells excised directly from the tumor
• They are expanded in culture using IL-2 while the patient’s immune system is being irradiated
• You can now insert the anti-tumor clones and let them run around to kill the tumor

If the tumor was a government, its as if you were creating an informant/hitman within the government to bring the whole thing down

Question 8

1. What are PD-4 and CTLA?
2. What would there uses be as they relate to monoclonal antibodies?

Answer 8

1. They are CTL checkpoint inhibitors (block cytotoxic activity when activated)
2. Can make a monoclonal Ab against PD-1 which binds and blocks CTL inactivation

Recall that PD-1 reduces cytotoxic activity

• Can also make ipilimumab to block CTLA-4

Recall CTLA-4 is a downregulator of CTL activity

Question 9

What are some cancer therapies that could be used using T-cells?

Answer 9

T cell methods:

• A vaccine that uses the patient’s own DCs with a fusion protein containing the cancer TAA
• New ones also include epitopes with a higher affinity to the MHC or TCR
  
  • Mostly associated to cytokine TNF, where macrophages and neutrophils can come in and eat away.

Question 10

What are some cancer therapies that might include use of antibodies?

Answer 10

Antibody possible therapies:

• Activate complement
• Invoke ADCC
• Tagged with a poison (immunotoxins)
• Also can use antibodies to growth factors to stop self-stimulating (autocrine signaling)
  
  • Example is anti-IL-2 receptor in T lymphomas
• Herceptin is another, a mAb to HER2 on breast cancer

Question 11

How would a BCG vaccine cause tumor regression?

Answer 11

Recall: BCG vaccine is designed to prevent TB

1. Injected directly into the tumor
2. Get a delayed-type hypersensitivity (Type IV) reaction to the BCG (in lining of bladder)
3. Tumor is killed by innocent bystanders & angry macrophages

Question 12

What are some of the prospects and problems in using monoclonal antibodies to treat tumors?

Answer 12

Prospects:

• Can use passive antibodies to target TAAs that the body wouldn’t otherwise make Ab to.
  
  • Again, this is Herceptin and anti-VEGF

Problems:

• Passive use of monoclonal antibodies also affect normal cells that produce the TAA
• Cells can become resistant to complement or can inactivate it as well.
• Expensive