topic 7 Flashcards
What are 3 things that could be changed in a tumor cell that would make it recognizable to a t cell?
Altered self-antigen
Aberrant or overexpressed self-antigen
When a virus causes a tumor, sometimes those tumor cells will have remnants of the virus which will be recognized.
What is cross-priming or cross presentation?
Tumor cells often aren’t great APCs
When they die, part of them will be taken up by DCs.
In the DCs, most will end up in MHC class II but some will be cross presented and end up in MHC class I which will lead to proliferation and differentiation of CD8 T cells which can kill the tumor cells directly.
What are some ways in which tumors can evade an immune response?
They might not produce tumor antigen and thus can’t be recognized
They might down regulate or a have a mutation in Class I MHC making it so they can’t be recognized
They might directly secrete immunosuppressive proteins which inhibit T cell activation.
They dont’ have an co-stimulators which make it seem like they’re self-cells.
They can endocytose Ab/antigen complex and thus destroy the antigen
What is immuno-editing?
When a tumor cell arises, many immune cells can recognize them and kill them. However, some survive, and then variant tumor cells that are resistant arise. With time, more and more arise. Eventually, one might completely escape killing and be able to spread unchallenged.
What are 3 types of cancer immunotherapy, how do they work/what are the results?
Passive immunity-tumor specific t cells or antibodies are put into cancer patients and they kill tumor cells.
Active T cell immunity by enhanced dendritic vaccines-load up DCs with tumor antigens to give a boost to the t cells once they see the DCs–>Activtion of tumor specific t cells and killing of tumor cells
Active immunity enhanced by blockade of t cell inhibitory molecules. Block the inhibitor receptor of a t cell so a tumor cell ligand can’t bind to it and thus block killing. –>Activtion of tumor specific t cells and killing of tumor cells
What is an example of passive immunity using monoclonal antibodies?
Rituximab-Binds to CD20 which is on most tumor cells with its FAB and binds to NK cells with Fc portion.
What are 3 examples of how antibodies can be used in passive immunity?
Use antibody to bind tumor cell and have its Fc portion bind NK cells
Design an antibody whose Fab portion will bind tumor cell but instead of an Fc portion, put a toxin that will be endocytosed and destory the tumor cell
Design an antibody whose fab portion binds tumor cell but instead of an Fc portion, put a radionuclide that will be endocytosed and have radiation kill cell and surrounding cells.
How does passive immunity using adoptive t cell immunotherapy work?
Part of a tumour is excised then fragmented so separate t cells can be cultured with IL-2 which causes them to proliferate. The different assays are tested for specific tumor recognition, then proliferated again. Pt. is lymphodepleted (take out existing t cells so new ones can take over). Tumor specific t cells are infused.
What are genetically modified tumor-reactive t cells?
Now that we know which genes encode TCRs, you can insert genes into that portion of the DNA which make it recognize tumor specific antigens so they have an endogenous TCR and a tumor specific TCR. After mixing them with normal t cells, they will circulate and be transduced (spread to other cells)
This allows you to skip most of the steps of adoptive t cell immunotherapy and simply engineer t cells that will recognize tumor and infuse them into the patient.
How do CAR receptors work, how were they developed, and what do they allow us to do?
The Fab portion of a monoclonal antibody that recognized tumors was fused with proteins that lead to the activation signal cascade in t cells (costimulators, etc.). This receptor was induced into t cells.
Normally a t cell is required to recognize an MHC and can be inhibited, but in this case, the CAR recognizes the tumor directly and the CAR directly activates the T cell so that it will release cytokines as well as perforin and granzymes. It makes it harder for a tumor cell to inhibit it.
What are some limitations to passive immunotherapy?
Antibodies rely on other immune cells (unless they’re toxin conjugated or radio-labeled)
Adoptive t cell transfer still require costimulation for function and long term t cell persistence
CAR T cells gaurantee costimulation but can only recognize antigens that are on the surface of tumors (don’t see MHCs)
How does active immunity enhanced by blockade of t cell inhibitory molecules work? What are some inhibitory receptors on T cells that are targeted?
Normally, when a t cell binds to another cell, an inhibitory ligand on the cell will lead to no expansion, etc. of t-cell.
In this therapy, monoclonal antibodies were created that would block the binding of the inhibitory ligand (PDL-1) to inhibitory receptors such as PD-1 and CTLA-4 (binds the same ligand as CD28, costimulator B-7 but leads to an inhibitory response. It has a higher affinity for B-7 than CD28).
by putting these antibodies into patients, tumors are unable to use these receptors to block expansion of proliferation of these tumor specific t cells.
Can cause some autoimmunity.
