L10 Tumor immunology

Question 1

Immune surveillance + tumor cell mutation > selection of the fittest mutants and survive = Cancer immunoediting

• Describe what is involved in immune surveillance.

Answer 1

• NK cells and T cells constantly identify and kill precancerous and cancerous cells > high mutation rate of cancerous cells > selection of tumor variants capable of escaping immunologic detection and elimination

Question 2

Give examples of tumor cell mutation to escape from immunologic detection.

Answer 2

constant mutation and recruitment of Treg

Question 3

Tumors with T cell infiltration shows better prognosis with increased overall survival and progression-free survival, also _____________________.

Answer 3

Better response to chemotherapy

Question 4

Tumor antigens are either expressed on cell surface/ released into circulation

Give examples to
1. Tumor-specific Ag (expressed by tumor cells only)

Answer 4

1. Tumor-specific Ag
   - Viral Ag - e.g. HPV, EBV (cancer vaccines can be used)
   - Mutated proteins with tumorogenesis, e.g. mutated p53 (but not useful for diagnosis)

Question 5

Tumor antigens are either expressed on cell surface/ released into circulation

Give examples to
2. Tumor-associated Ag (expressed by tumor and normal cells)

Answer 5

Tumor-associated Ag

1. Normal proteins expressed by cell lineage of tumor cells e.g. CD20 in B-cell-NHL
2. Overexpressed normal proetins, e.g. HER2 in CA breast
3. Abberantly expressed normal proteins
   
   • Oncofetal Ag (normally expressed in fetal age), e.g. CEA carcinoembryonic Ag) in CA colon, AFP (alpha-fetoprotein) in HCC
     - Cancer testis Ag: normally epressed in testis , but abberantly expressed outside e.g. MAGE-1

• use cancer vaccines

Question 6

Tumor markers can be used for diagnosis, disease monitoring and __________________.

Answer 6

Tumor localization

Question 7

Give an example of how tumor markers can be used to make a diagnosis.

Answer 7

CD10 in B-ALL (acute lymphoblastic leukemia)

Question 8

Give an example of how tumor markers can be used to monitor disease.

Answer 8

CEA carcinoembryonic Ag; AFP can be monitored

not for diagnosis, increased in other benign conditions e.g. cirrhosis

Question 9

Give an example of how tumor markers can be used to localise the tumor.

Answer 9

Radio-labelled Ab against CEA in mCRC > CT scan

Question 10

Therapeutic Ab is used in tumor identification. The Ab is Ag-specific.
Give examples of the Ab and their uses.

Answer 10

1. Unconjugated therapeutic Ab (e.g. trastuzumab)
   - for tumor signalling inhibition
   - for cytotoxic killing by ADCC (directs NK cell to kill tumor cells)
2. Conjugated therapeutric Ab with immunotoxin (e.g. tranzutumab emtansine)
   - for killing tumor cells
   - or radioisotype :kill tumor cells and neighboring tumor cells

Question 11

How is CAR-T cell target (engineered) used for identifying tumor antigens? (mechanism?)

Answer 11

Chimeric antigen receptor (CAR)

1. Extracellular portion: variable domain of Ab (tumor Ag specific)
2. Cytoplasmic portion: T-cell signalling domain for T cell proliferation

Question 12

T cells are engineered externally to express CAR. Give an example and state the side effects.

Answer 12

Anti-CD19 CAR-T cells for B-ALL

- side effects: fatal cytokine release syndrome: increase release of inflammatory cytokines

Question 13

How does cancer vaccine work?

Answer 13

Tumor Ag is loaded into immature DC, add GM-CSF and infuse back.

1. 1st set of differentiating cytokines: CM-CSF,IL-4
2. tumor Ag loading to immature DC
3. 2nd set of activating cytokines: TNF-alpha, IL-1beta > DC maturation

Question 14

Sipuleucel-T is for advanced Ca prostate.
Immature DC + prostatic acid phosphatase (PAP) + CM-CSF.
Example of ?

Answer 14

Cancer vaccine

Question 15

What are the examples for cancer vaccine for cancer testis antigens (CTA)?

Answer 15

MAGE-1, NY-ESO-1

Question 16

Immune evasion mechanisms include low immunogenicity, tumor-induced immunosuppresiona and immune checkpoints.
Describe the mechanism of low immunogenicity.

Answer 16

1. Loss of all MHC class I > not susceptible to CTL but to NK only
2. Loss of particular MHC that presents tumor Ag: not susceptible to CTL or NK
3. Lack of costimulatory molecules (CD80/86 =BK7?) > poor T cell activation

Question 17

Solutions to low immunogenicity? (3)

Answer 17

1. Cancer vaccines: tumor Ag-loaded DC
2. Type 1 interferon: increase MHC class I expression
3. IL-2L essential for T cell activation, increase intratumoral T cells, but increase risk of bacterial infection (impairs neutrophil chemotaxis) and fatal capillary leak syndrome

Question 18

In tumor-induced immunosuppression, tumor cells release immunosuppressive factors like ___________ to _________, _____ and _____ to _________.

Answer 18

1. TGF-beta to induce Treg

2. IL-10 and IDO (indoleamine 2,3-dioxygenase) to deplete tryptophan > T cell cycle arrest and apoptosis

Question 19

How can tumor-induced immunosuppression be solved?

Answer 19

Ex-vivo activation of Tcells and NK cells.

• Tumor-infiltrating lymphocytes (CTL) > +anti-CD3 and IL-2 to stimulate T cells > CTL
• Peripheral blood NK > IL-2 to stimulate NK cells > LAK (lymphokine activated killer cell)

Question 20

Tumor cells escape immunity by interfering immune checkpoints. Briefly describe how.

Answer 20

1. PD-L1 from tumor cells binds to PD-1 on T cell to reduce T effector cell activation
2. CLTA-4 from T cells bind to CD80/86 on APC > reduce naive T cell activation (normal regulatory mechanism)

Question 21

Ipilimumab is ?

Answer 21

A CTLA-4 inhibitor

Question 22

Pembrolizumab and Atezolizumab are _______ and ________ respectively.

Answer 22

PD-1 inhibitor

PD-L1 inhibitor

Question 23

Tumor-induced privileged site means tumor cells secrete __________ to create a physical barrier in the body.

Answer 23

collagen