Immune Therapy Overview

Question 1

What is tumor immunology

Answer 1

It is the manipulation of the immune system to recognize and destroy tumor cells

Question 2

Neutrophils

Answer 2

Fastest cell in the body of a woman

Question 3

What is the function of macrophages in addition to phagocytose foreign particles

Answer 3

They are antigen presenting cells and they also release cytokines to signal other cells the area of problem

Question 4

What is the function of natural killer cells

Answer 4

These are activated by the encounter of infected cells or tumor cells.

They kill these cells.

They secrete IFNy (a cytokine)

Question 5

What does T cells do

Answer 5

There are 2 types of T cells

1. CD4+ T cells are helper T cells
2. CD8+ T cells are cytotoxic T cells

Question 6

What is the association of inflammation with tumor

Answer 6

It is a 2 edged sword: Inflammation is requried to kill tumor but it can also lead to the development of tumor.

Acute inflammation is an established result in tumor destruction whereas chronic inflammation is a contributing factor to tumor growth or to tumor development.

Question 7

What are the characteristics of acute inflammation and chronic inflammation

Answer 7

Acute inflammation: Within minutes, vasodilation, vascular permeability, leads to recruitment of neutrophils

Chronic inflammation: Long term, leads to fibrogenesis, angiogenesis, tissue remodeling. It allows recruitment of macrophages and lymphocytes

Question 8

Explain how asbestos can lead to mesothelioma

Answer 8

Asbestons particles are fine enough that they can be inhlaed. We they enter our body, macrophages of the lungs phagocytose them, but these particles cannot be broken down. Phagocytosis by macrophages causes inflammation which leads to the development of cancer. Also these particles accumulate in our body since they are not biodegradable

Question 9

What is Immunoediting

Answer 9

Three E’s:

1. Elimination - immune surveillance
2. Equilibrium
3. Escape

Question 10

What is immune surveilance

Answer 10

Destroy the cells that are likely to become tumors. This is done by the immune system to avoid tumor development which can lead to harm

Question 11

What does T cells do

Answer 11

T cells recognize antigen via the T Cell Receptor. This antigen in the context of T cells is a peptide derived from degraded protein. To be recognized as an own, the antigen must be presnted as MHC (Major Histocompatibility Complex)

Question 12

What is MHC

Answer 12

There are 2 types:

1. MHC class I: expressed most nucleated cells, peptides are presented to CD8 T cells
2. MHC class II: Expressed by professional antigen presenting cells (like macrophages, dendritic cells, B lymphocytes). These peptides are presented to CD4+ T cells

Question 13

What kind of antigens can be presented by tumor cells

Answer 13

Both MHC class I and II

Question 14

Neoantigens

Answer 14

Question 15

What is a Neoantigen

Answer 15

Chimeric proteins or mutations that make weird proteins that used to be normal body protiens

Question 16

What do you need to activate a T cell fully? What is it called when you dont fully activate a T cell

Answer 16

TCR + co receptor + cytokines

If you only stimulate the T cells with TCR (T cell receptors) then the cell is not fully activated and we have a phenomena called Anergy

Question 17

What is Anergy

Answer 17

It is a state of unresponsiveness

Question 18

What was the diagram that he showed us regarding this phenomena

Answer 18

Question 19

Explain the process of elimination (or summarize the process of elimination)

Answer 19

1. T cells recognize the tumor antigens presented by MHC
2. MHC is expressed by tumor cells or macrophages/dendritic cells
3. CD8+ T cells and NK T cells destroy the tumor

Question 20

Compare and contrast the NK T cells and CD8+ T cells

Answer 20

CD8+ cells need MHC class 1 to recognize the tumor and destroy it whereas on the other hand NK cells recognize the lack of class 1 and then identify and destroy the tumor.

Question 21

Explain how the NK cells know when to destroy a cell and when not to

Answer 21

NK cells have a combination of Activating Receptors (AR) and Inhibitory Receptors (IR). AR recognizes a variety of class of ligands on target cells (or tumor cells) whereas IR recognzies the non polymorphic residues of MHC class 1.

It is important to realize how these AR and IR work together. IR are dominant over AR. Loss of MHC 1 is going to lead to the loss of IR and this will activate the NK cells to destroy that specific cell or tissue.

Question 22

How are tumor cells destoryed by the NK cells

Answer 22

One of the things what tumor cells like to do is to down regualte their MHC class 1. This takes away the IR and this causes the NK cells to kill the tumor cells

Question 23

Explain the concept of elimination vs equilibrium

Answer 23

This concept explain that some tumor cells show enough of MHC class 1 that is not high enough to avoid the CD8+ T cells but it is high enough to avoid the NK cells so the tumor is in an equilibrium state where the state of apoptosis and proliferation equals. The tumor remain in our body for several years but does not grow in size

Question 24

How does tumor cells escape the immunesystem

Answer 24

They develop what we call immunosuppressive microenvironment. Also some tumors can escape immunologial control by developing immunologic check points

Question 25

What is an Immunosuppressive microenvironment

Answer 25

There is a group of CD4+ T cells that express high levels of FoxP3 transcription factor and CD25. They are involved in down regulating the immune response by suppressing the activity of T cells, macrophages and other immune cells. Other ways the tumor cells avoid immune system when expressing immunosuppressive microenvironment is by reducing MHC class 1 and lacking the co receptor ligands.

Question 26

What are immunologic checkpoints

Answer 26

1. Repeated T cells stimulation leads to anergy. 2. Cancer cells can express 2 important proteins that can downregulate the activity of T cells and these 2 proteins are PD1 and CTLA4

Question 27

Whats explained here in this diagram

Answer 27

This is an important point to remember. Even though the cancer cells express PD1 and CTLA4 and down regulate the activity of the immune system, they still express MHC class 1 which can be identified by the T cells and it can turn the T cells on. However, when there is Activating signal for AR, at the same time there is an inhibitory signal from the IRs due to PD1 and CTLA4. Since inhibitory signals are dominant this leads to T cells in anergy state.

Question 28

Explain CTLA 4 in detail

Answer 28

It is a co receptor on activated T cells which is basically an off switch. When a ligand binds to this co receptor it turns off the activity of the T cells. The class of ligands that binds to CTLA 4 are called B7-1 and B7-2. CTLA 4 blocks CD28 stimulation.

Question 29

Name the anti CTLA 4 monoclonal antibody that is used to treat cancer. What kind of cancer is treated using this antibody

Answer 29

Ipilimumab. Used to treat metastatic melanoma.

Question 30

Is BD7-1/2 ligand for tunring on T cells or is it for turning off T cells. What other ligand has the same function. What does this phenomena lead to

Answer 30

They are for both. C28 This leads to the fact that we have AR and IR on the T cells competing for the same lignads that are present on the antigen presenting cells

Question 31

What is an Ipilimumab

Answer 31

It is a check point inhibitor

Question 32

Explain how does CTLA4 works and then how do we exploit the mechanism of CTLA4 to use ipilimumab to treat metastatic melanoma

Answer 32

Picture 1: Antigen presenting cell (APC) comes to an inactive T cell, expresses MHC class 1 and the ligands required for activation CD28 and B7-1/2. This T cell is not activated. Picture 2: When this T cell is activated the CTLA4 is now expressed on the surface. It will bind to the B7-1/2 ligand on APC and get turned off. Picture 3: We use ipilimumab to inhibit CTLA4 so the T cell remains active and helps in killing the metastatic tumor.

Question 33

Explain PD1

Answer 33

It is an inhibitory co receptor on T cells, just like CTLA4. Its ligands are different however, it binds to PD-L1 and PD-L2. These ligands are primarily expressed on dendritic cells Nivolumab is an anti PD1 antobibody that is in clinical trials

Question 34

What are some of the examples he gave us for treatment of different kinds of cancer

Answer 34

IL-2 was given to a patient with metastatic melanoma who failed all other treatments. For bladder cancer, they injected a mycobacterium in the baldder via a catheter and allowed the bacterium to cause an immune response in the bladder. This caused acute inflammation in the bladder and the immune response destroyed the cancer cells as well as the bacteria. This is called BCG therapy.

Question 35

Summary slide of elimination, equilibrium and escape

Answer 35

Question 36

What are depleting antibodies and what is an example of it

Answer 36

Antibodies that kill target cells (such as tumor cells). Anti CD20 antibodies are used in several cancers. CD 20 is used to B cells. If we have cancer of B cells, we give anti CD20 all of the B cells will die

Question 37

What are the three ways we can get immunity from certain type of cancers

Answer 37

Question 38

Acute inflammation vs chronic inflammation, which one if good for us and which one is good for the tumor

Answer 38

Acute inflammation is good for us, chronic inflammation is good for the tumor