CCR5/CCL5 Interaction in Cancer- and T-Cells
Revision of our earlier 'mumblings', I was a bit confused about roles.
Hopefully this helps a little bit, neither of us is a immunology specialist (o8>
CCL5 is expressed and secreted by stromal cells and cancer cells.
CCL5 is expressed in many diseases.
CCR5 is expressed on T cells, macrophages, dendritic cells .. and cancer cells.
CCR5 interacts with CCL5 (besides others).
We see the CCR5/CCL5 interaction as an oscillating system,
where CCL5 is inducing CCR5 activity[1, ..].
Since it is also known that tumor cells induce CCL5 expression[2]
in stromal cells we have the oscillation (interaction) complete,
meaning tumor growth and metasasis can proceed.
Any molecule interfering with this system can be seen as a modulator.
[1] CCR5 Antagonist Blocks Metastasis of Basal Breast
Cancer Cells
http://cancerres.aacrjournals.org/content/can...9.full.pdf
[2] Pancreatic cancer cells activate CCL5 expression in mesenchymal stromal cells through the insulin-like growth factor-I pathway
https://www.sciencedirect.com/science/article...9309008497
Our earlier confusion came from the fact that PRO 140
also partially blocks the immune cell's CCR5 receptor,
which is our MOA as an HIV-1 R5-strain entry inhibitor.
Here we have learned that an infection like the flu
or a forced immune response like a flu-shot
reduces PRO 140's CCR5 occupation. Hence we have experienced a viral load rebound.
After increasing the dosage, this has been resolved.
This implies higher CCR5 count or expression on T-Cells during an infection
due to the inflammatory response.
Gladly, CCR5 is not the single method for the immune system
to respond, otherwise all of our long years patients would have died
due to simple everyday infections.
How come the immune system is more efficient
when a CCR5 blocker is given?
This was the latest surprise being reported, AFAIK by the German trial(?)
Questions arise from the T-Cell and cancer cell interaction.
For one, PRO 140 blocks both their CCR5 receptor partially.
This reduces the cancer cell's growth and metasasis, while the T-Cells
are still mostly operative.
Therefor the T-Cell is not being made invisible to the cancer cell,
but the cancer cell's CCR5 receptors can not bind to CCL5 anymore.
However, since the T-Cell's CCR5 receptor is also blocked,
the CCL5 pathway alone won't make them more effective against cancer.
Maybe it is a 'simple' balance of power observed here,
where the immune system is now more effective against less
active cancer cells, stopped from growing etc.
This is an open question, but great to have been observed.
Misiu:
Exactly!
Therefor we have two achievements here:
1) Stop spreading / metastasis cancer via disruption of CCL5/CCR5 Oscillation
2) Improve immune response to kill cancer cells
Revision of our earlier 'mumblings', I was a bit confused about roles.
Hopefully this helps a little bit, neither of us is a immunology specialist (o8>
CCL5 is expressed and secreted by stromal cells and cancer cells.
CCL5 is expressed in many diseases.
CCR5 is expressed on T cells, macrophages, dendritic cells .. and cancer cells.
CCR5 interacts with CCL5 (besides others).
We see the CCR5/CCL5 interaction as an oscillating system,
where CCL5 is inducing CCR5 activity[1, ..].
Since it is also known that tumor cells induce CCL5 expression[2]
in stromal cells we have the oscillation (interaction) complete,
meaning tumor growth and metasasis can proceed.
Any molecule interfering with this system can be seen as a modulator.
[1] CCR5 Antagonist Blocks Metastasis of Basal Breast
Cancer Cells
http://cancerres.aacrjournals.org/content/can...9.full.pdf
Quote:
CCL5 can be expressed and secreted either by breast cancer cells (9 – 12) or
by nonmalignant stromal cells at the primary or metastatic sites (13).
..
Accordingly, inhibition of CCR5 by a peptide antagonist reduced leukocyte
infiltration and reduced tumor growth after subcutaneous injection of
410.4 cells into immunocompetent mice (16).
[2] Pancreatic cancer cells activate CCL5 expression in mesenchymal stromal cells through the insulin-like growth factor-I pathway
https://www.sciencedirect.com/science/article...9309008497
Quote:
Here we demonstrate that CC chemokine ligand 5 (CCL5) expression was increased in MSCs co-cultured with pancreatic cancer cells (PCCs), and this activation was dependent on extracellular insulin-like growth factor (IGF-I). Moreover, CCL5 induction in MSCs was required for the activation of IGF-I pathway in PCCs. These results reveal a link between the IGF-I pathway in PCCs and CCL5 pathway in MSCs through the interaction of those cells.
Our earlier confusion came from the fact that PRO 140
also partially blocks the immune cell's CCR5 receptor,
which is our MOA as an HIV-1 R5-strain entry inhibitor.
Here we have learned that an infection like the flu
or a forced immune response like a flu-shot
reduces PRO 140's CCR5 occupation. Hence we have experienced a viral load rebound.
After increasing the dosage, this has been resolved.
This implies higher CCR5 count or expression on T-Cells during an infection
due to the inflammatory response.
Gladly, CCR5 is not the single method for the immune system
to respond, otherwise all of our long years patients would have died
due to simple everyday infections.
How come the immune system is more efficient
when a CCR5 blocker is given?
This was the latest surprise being reported, AFAIK by the German trial(?)
Questions arise from the T-Cell and cancer cell interaction.
For one, PRO 140 blocks both their CCR5 receptor partially.
This reduces the cancer cell's growth and metasasis, while the T-Cells
are still mostly operative.
Therefor the T-Cell is not being made invisible to the cancer cell,
but the cancer cell's CCR5 receptors can not bind to CCL5 anymore.
However, since the T-Cell's CCR5 receptor is also blocked,
the CCL5 pathway alone won't make them more effective against cancer.
Maybe it is a 'simple' balance of power observed here,
where the immune system is now more effective against less
active cancer cells, stopped from growing etc.
This is an open question, but great to have been observed.
Misiu:
Quote:They also notice this immune improvement ,cancer cells death increase etc , I am not sure if they know 100% why all this is happening .,
As a clinician I am happy with that , and as dr Pestell said few times that we still learning why the positive things are happening here ..
It is really new and very exciting in cancer studies .
Exactly!
Therefor we have two achievements here:
1) Stop spreading / metastasis cancer via disruption of CCL5/CCR5 Oscillation
2) Improve immune response to kill cancer cells
