Immune Therapy Overview Flashcards
What is tumor immunology
It is the manipulation of the immune system to recognize and destroy tumor cells
Neutrophils
Fastest cell in the body of a woman
What is the function of macrophages in addition to phagocytose foreign particles
They are antigen presenting cells and they also release cytokines to signal other cells the area of problem
What is the function of natural killer cells
These are activated by the encounter of infected cells or tumor cells.
They kill these cells.
They secrete IFNy (a cytokine)
What does T cells do
There are 2 types of T cells
- CD4+ T cells are helper T cells
- CD8+ T cells are cytotoxic T cells
What is the association of inflammation with tumor
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.
What are the characteristics of acute inflammation and chronic inflammation
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
Explain how asbestos can lead to mesothelioma
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
What is Immunoediting
Three E’s:
- Elimination - immune surveillance
- Equilibrium
- Escape
What is immune surveilance
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
What does T cells do
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)
What is MHC
There are 2 types:
- MHC class I: expressed most nucleated cells, peptides are presented to CD8 T cells
- MHC class II: Expressed by professional antigen presenting cells (like macrophages, dendritic cells, B lymphocytes). These peptides are presented to CD4+ T cells
What kind of antigens can be presented by tumor cells
Both MHC class I and II
Neoantigens
What is a Neoantigen
Chimeric proteins or mutations that make weird proteins that used to be normal body protiens
What do you need to activate a T cell fully? What is it called when you dont fully activate a T cell
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
What is Anergy
It is a state of unresponsiveness
What was the diagram that he showed us regarding this phenomena
Explain the process of elimination (or summarize the process of elimination)
- T cells recognize the tumor antigens presented by MHC
- MHC is expressed by tumor cells or macrophages/dendritic cells
- CD8+ T cells and NK T cells destroy the tumor
Compare and contrast the NK T cells and CD8+ T cells
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.
Explain how the NK cells know when to destroy a cell and when not to
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.
How are tumor cells destoryed by the NK cells
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
Explain the concept of elimination vs equilibrium
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
How does tumor cells escape the immunesystem
They develop what we call immunosuppressive microenvironment. Also some tumors can escape immunologial control by developing immunologic check points
What is an Immunosuppressive microenvironment
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.
What are immunologic checkpoints
- Repeated T cells stimulation leads to anergy.
- Cancer cells can express 2 important proteins that can downregulate the activity of T cells and these 2 proteins are PD1 and CTLA4
Whats explained here in this diagram
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.
Explain CTLA 4 in detail
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.
Name the anti CTLA 4 monoclonal antibody that is used to treat cancer.
What kind of cancer is treated using this antibody
Ipilimumab.
Used to treat metastatic melanoma.
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
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
What is an Ipilimumab
It is a check point inhibitor
Explain how does CTLA4 works and then how do we exploit the mechanism of CTLA4 to use ipilimumab to treat metastatic melanoma
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.
Explain PD1
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
What are some of the examples he gave us for treatment of different kinds of cancer
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.
Summary slide of elimination, equilibrium and escape
What are depleting antibodies and what is an example of it
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
What are the three ways we can get immunity from certain type of cancers
Acute inflammation vs chronic inflammation, which one if good for us and which one is good for the tumor
Acute inflammation is good for us, chronic inflammation is good for the tumor
