PHD - Immune Response to Tumor

Question 1

What is the mechanism by which type II responses (induced by a tumor) function to downregulate an immune response?

Answer 1

Function to upregulate T_regs to block APCs, CD8+ and CD4+

Question 2

What is the mechanism of action of granzyme B?

Answer 2

Granzyme B functions to activate the apoptosis pathway.

1. Enters the cell
2. Cleaves BID to induce Bax and BAK
3. Releases cytochrome from mitochondria
4. Formation of apoptosome
5. Activation of caspase-9

Question 3

List the cytokines responsible for inducing naive CD4+ T-cells to become each of the following:

1. T_H1
2. T_H17
3. T_reg
4. T_H2

Answer 3

1. TH1 - IL-12 and IFN-gamma
2. TH17 - IL-23
3. Treg - TGF-beta
4. TH2 - IL-4

Question 4

Differentiate between type 1 and type 2 environments that are induced by a tumor in immunosurveillance.

Answer 4

Type 1 - ideal for tumor killing

Type 2 - immunosuppressive, to prevent tumor death

Question 5

What are the steps to chimeric antigen receptor therapy?

Answer 5

1. T-cell isolation from patient
2. Transfection with tumor antigen
3. Reintroduction into the body
4. Monitor patient

Question 6

What is Tumor Infiltration Lymphocytes (TIL) therapy?

Answer 6

Removal of T-cells from a tumor, upregulating them, and then re-injecting them back into the tumor in higher numbers

Question 7

What is the primary function of chimeric antigen receptor therapy in cancer?

Answer 7

Used to promote T-cell responses to a tumor through grafting monoclonal antibody specificity onto a T-cell

Question 8

What are some mechanisms that are being used to upregulate the immune response in cancer immunotherapy?

Answer 8

Anti-CTLA-4 (ipilimumab) and anti-PD-1 (pembrolizumab)

CTLA-4 binds to B7, which prevents T-cells from being activated (blocking this would allow T-cells to be activated against tumor antigen)

PD-1 prevents Treg cells from undergoing apoptosis (blocking this would allow T-cells to react with tumor antigen)

Question 9

What cell immunosurveillance promotes type II response through production of arginase and ROS to induce immunosuppression?

Answer 9

Myeloid-derived suppressor cells (MDSCs)

Question 10

What are the two receptors that are activated during the extrinsic pathway of apoptosis?

Answer 10

1. TNF-related apoptosis induced ligand (TRAIL) receptor
   
   1. TRAIL secreted by normal tissue cells –> causes tumor cells to undergo apoptosis
2. Fas receptors (CD95)
   
   1. Fas binds Fas-L and induces the extrinsic pathway of apoptosis (activates caspases)

Question 11

True or False: Tumors that test positive for CD8+ T-cells have a better prognosis than those who don’t.

Answer 11

True

Question 12

Explain how point mutations can lead to activation of lymphocytes in immunosurveillance.

Answer 12

T-cells would not respond to self-antigens because there is an alteration in the protein. This leads to activation of a T-cell that is no longer “self.”

Question 13

What are two functions of granzymes?

Answer 13

1. Apoptosis
2. Inflammation - recruits macrophages to cause inflammatory response

Question 14

What lymphocytes are activated in immunosurveillance in response to a cancer?

Answer 14

CD8+ T-cells via MHC I

Question 15

How are Tumor activating macrophages (TAMS, M2 Macrophage) activated?

Answer 15

Via IL-4, IL-13, and TGF-beta

• IL-4 –> Th2
• IL-13 –> Th17
• TGF-beta –> Treg

Question 16

What cells of the innate immune system respond to a tumor?

Answer 16

Natural Killer Cells

Question 17

Explain how dendritic cell vaccines can be used as a prophylactic to cancers.

Answer 17

Injection of DCs into a patient is a form of passive immunity. This allows for a pre-existing immunity to a tumor cell, which can eliminate a “rogue” cancer cell before it can divide.

Question 18

What is the chemoatrractant that causes phagocytes to migrate toward apoototic debris?

Answer 18

Phosphatidylethanolamine (PE) induces the attraction of phagycotes to apoptotic cells

Question 19

Differentiate between passive immunotherapy and adoptive transfer therapy in cancer treatment.

Answer 19

• Passive immunotherapy - monoclonal antibodies activate host defenses and deliver toxins
• Adoptive transfer therapy - full cells, expansion of anti-tumor effector cells, and administration of expanded immune cells to target tumor cells

Question 20

What specific granzyme is used by CD8+ cells to induce apoptosis?

Answer 20

Granzyme B

Question 21

Explain how HPV can be prevented from inducing cancer through immunosurveillance.

Answer 21

Cells infected with HPV E6 and E7 proteins will express HPV proteins that can be recognized by T-cells and eliminated.

Question 22

What drug is often given with CAR therapy? Why? What is the mechanism of action of the drug?

Answer 22

Tocilizumab

This drug lowers IL-6

Also used to treat RA

Question 23

What is the function of TAMS2/M2 and within what type of immunosurveillance response do they participate?

Answer 23

Activates type II surveillance

Essential to angiogenesis

Question 24

Is TIL therapy is an example of passive immunotherapy or adoptive transfer therapy?

Answer 24

Adoptive transfer therapy

TIL involves transfer of full T-cells

Question 25

What is the mechanism by which an activated T-cell kills a tumor cell in immunosurveillance?

Answer 25

Activated T-cells produce perforins and granzyme B to the APC in order to induce apoptosis.

Question 26

Activation of what lymphocytic receptors allows tumor cells to bypass immunosurveillance?

Answer 26

CTLA-4 and PD-1

Question 27

What are the three primary mechanisms by which tumor cells can alter the APC and evade immunosurveillance?

Answer 27

1. Preventing expression of tumor antigen 2. Expressing stimulators to activate PD-1 and CTLA-4 on T-cells 3. Downregulation of MHC-I expression on APC

Question 28

For CD8+ T-cells, what are the three things needed to induce its differentiation and activation?

Answer 28

1. Class I MHC peptide presentation 2. Co-stimulation 3. CD4+ T-cell assistance

Question 29

Which MHC group is activated during an immunosurveillance response to cancer elimination?

Answer 29

MHC I (CD8+ mediated)

Question 30

In tumor elimination, what is happening in the first and second phases?

Answer 30

* Phase I - tumor growth \< tumor cell death * Tumor antigens displayed * Increaed tumor cell death by immune cells * Phase II - tumor cell growtn = tumor cell death * Variants survive elimination - genetic instability --\> mutation * Acquisition of resistance * Phase III - tumor cell growth \> tumor cell death * Evasion of CD8+ T-cells

Question 31

What is the function of myeloid-derived suppressor cells (MDSC)?

Answer 31

* Suppress the innate and adaptive anti-tumor immune response. * Promote tumor growth via downregulation of T-cells by producing arginase and ROS. * Induce Treg cells

Question 32

When exposed to each of the following cytokines, what does a CD4+ T-cell differentiate into: 1. IL-12 and IFN-gamma 2. IL-23 3. IL-4 4. TGF-beta

Answer 32

1. T_H1 2. T_H17 3. T_H2 4. T_reg

Question 33

Name the lymphocytes that produce each of the following cytokines: 1. IFN-gamma 2. TGF-beta, IL-10, and CTLA-4 3. IL-4, IL-5, and IL-13 4. IL-17, IL-6, TNF-alpha

Answer 33

1. T_H1 cell 2. T_reg 3. T_H2 cell 4. T_H17

Question 34

What is the mechanism of action of T_reg cells in tumor immunosurveillance?

Answer 34

Downregulate NK cells and promote tumor growth

Question 35

True or False: Thanks to immunosurveillance, many tumors remain dormant or regress.

Answer 35

True

Question 36

What are the three stages of cancer development?

Answer 36

1. Initiation - genomic changes in cell 2. Promotion - survival and clonal expansion of mutated cell 3. Progression - tumor growth and metastasis

Question 37

What cytokines do each of the following types of T-cells produce? 1. T_H1 2. T_H2 3. T_H17 4. T_reg

Answer 37

1. IFN-gamma 2. IL-4, IL-5, and IL-13 3. IL-17, IL-6, TNF-alpha 4. TGF-beta, IL-10, CTLA-4