Lecture 9 - Tumor Immunology (Maker)

Question 1

Two hit hypothesis

Answer 1

• need to lose both functioning alleles in order to get a cancer phenotype.
• could be 2 sporatic mutations or 1 inherited and 1 sporatic
• example: Rb gene in retinoblastoma

Question 2

Cancer Immunoediting

Answer 2

1. Elimination - immune system kills cancer
2. Equilibrium - equal rate of growth/death
3. Escape - tumor evades immune system

Tumor is able to adapt over time!

Question 3

How can a tumor evade the immune system?

Answer 3

1. Downregulate its MHC so no CTL cells recognize and come to attack.
2. Tumor secretes immunosuppressants such as TGF-B
3. Tumors lose expression of antigens
4. Antigens are present in tolergenic form
5. Antigen masking with mucus layer
6. Tumors do not express co-stim molecules or express inhibitory molecules (ex PD1 inhibits T cells)

Question 4

Basis of immunotherapy

Answer 4

Goal is to get active T cells. More active T cells = tumor shrinkage and recovery.

Question 5

T cell activation signals

Answer 5

1. MHC1 presents Ag to CD8
2. B7 on APC binds to CD28 on T cell.

need BOTH signals for activation

Question 6

Challenges of recognizing tumor Ags

Answer 6

1. Tumors have few specific Ags
2. Vaccines dont have a therapeutic benefit
3. Majority of tumor Ags are self or altered self
   Result is peripheral tolerance.
   Our bodies protect tumors from our immune system

Question 7

How to overcome peripheral tolerance?

Answer 7

Block inhibitors of the immune response to strengthen:

1. anti-tumor responses
2. responses limited by checkpoint inhibitors (Tregs, TGFB)

Question 8

CTLA4

Answer 8

receptor on T cell that binds to B7 with a higher affinity than CD28, so it acts as an inhibitor.
- this was the target for the first IM therapy. Ab that blocked this interaction. = metastatic melanoma

Question 9

PD1 /PD1-L

Answer 9

• basis for immunotherapy, inhibit T cell inhibitor

- PD1 is a receptor on T cells that binds to PD1L on APC to BLOCK immune response as a checkpoint against autoimmunity

Question 10

Specific immunotherapy techniques

Answer 10

1. Non-specific Immunotherapy, doesnt target tumor itself
   ex: aCTLA4, aPD1
2. Passive Immunization; targets tumor growth
   ex: Herceptin, Ab based
3. Active Immunotherapy; targets tumor specifically
   ex: vaccine based therapies.
4. Adoptive Immunotherapy; designer T cells
   ex: CAR-T

Question 11

Maker Lab Research

Answer 11

Metastatic colon cancer often goes to liver -> take out tumor and study expression.

• express LIGHT gene
• LIGHT + anti-CTLA4 completely cures cancer in animals