Re: How close did I get? Post from 2016 Part Two
Msg 1642 of 10962 at 9/6/2016 11:58:53 PM by
The following message was updated on 9/7/2016 11:42:36 AM.
I've been doing a bit of reading.
On every cell there is a the MHC protein on the surface that originated first inside the cell and migrates to the cell surface. It is the "self" identifier.
When our immune system is being developed early in life by the thymus gland, T-cells (thymus cells) that don't recognize this "self" protein are told to commit suicide by apoptosis. In this way the immune system eliminates any immune cells that might attack normal cells.
Moving along....an immune cell will not look at antigens on a cell if the MHC protein is of the correct "self" type. Observation and hypothesis...a cancer cell that might have antigens that would identify it as "not a good cell" but has the correct MHC molecule will be viewed as normal....tolerance.....cold tumor. So how do you get the immune system to recognize cancer?....you need an end around the MHC protein. When a cell dies normally it commits suicide by apoptosis.
Either internal DNA damage or an external death ligand is triggered by the immune cells.....causing apoptosis. But apoptosis is a programmed cell death that allows the cell to break apart into smaller sub cells to be absorbed by the body....with intact MHC "self" proteins....thus not causing an immune system to look at antigens....and starting an autoimmune disease. So apoptosis induced cell death is not a proper route for cancer targeting.....btw TVec causes apoptosis which may explain it's limitations.
What you need is autolysis:
You need the cancer cell to be destroyed by its own enzymes. In this manner the cell fragments and some of those fragments will not contain a MHC protein but will contain a non self antigen. Once those antigens are seen by the Antigen Presenting Cells (APC's) and Dedritic Cells (DC's) they can instruct Cytotoxic T-Cells and Natural Killer Cells (NKT's) to go after any other cancer cells that express those same non self antigens. Other immune cells may also start producing antibodies that lock on to those antigens marking those cells for death and thus bypassing the MHC molecule....systemic response.
PV-10 is a chemo style dye that because of its nature of the molecule only attacks acidic solid tumors through a process of molecular bending that makes the molecule hydrophilic and also hydrophobic at different points of tumor penetration. This allows PV-10 to enter the tumor cell's lysosomes to the point of bursting and causing autolysis....the tumor dies. Now as the tumor cells die and fragment the immune system kicks in....it activates....the bystander effect is started.
But there is a limit to the effect.
This reaction causes immune cells to output chemokines that do many things to activate the rest of the immune system and call for help. First those chemokines cause cells to raise up self protection ligands called PD-L1's. This is suppose to prevent normal cells from being targeted by the activated immune system by reaching up and pushing the switch off buttons on immune cells called PD-1's. Second Tregs follow the chemokine trail to the tumor to decide if enough bad cells warrant stepping aside or is it a false alarm in which they start shutting down the process. So there is this battle of who is right....the CD8+T (cytotoxic T) cells and APC's and DC's or the Tregs. There is also the PD-L1 expressions that hold back the immune system from the cancer cells who also reacted to the chemokines and put them in self defense mode.
So from how I see it....PV-10 causes autolysis...no cancer cell defense possible (like putting salt on a snail)....but if you also want systemic immunity then the bystander effect must kick in so quick that it doesn't allow tregs to shut it down so the immune system has a chance for antibody production which isn't affected by PD-L1. You do this by massive ablation.
But if the ablation wasn't large enough or quick enough then you are going to need help in keeping the bystander effect going....checkpoint inhibitors to allow immune cells to reach the tumor cells and Treg down regulators to prevent tregs from winding down the immune reaction....giving the immune system time to start antibody production and massive CD8+T cell clone production.
Update (/7/2016): When you have an organ transplant you match the MHC protein profile of the donor organ to the host as much as possible. You down regulate the immune system to tolerate the donor organ. When you are treating cancer systemically you are reversing this approach.....you are trying to up regulate the immune system and get past MHC tolerance of the tumor by the immune system. You are trying to tell the body the tumor is a donor organ that needs to be rejected.