I think, in only a few words, you extract the prec

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I think, in only a few words, you extract the precise reason why PD-L1 is upregulated in from 30-90 days after leronlimab is started.

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MSI tumors are more often hot because the mismatch repair of DNA will signal to the immune system to destroy tumor cells.

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It might not be the signaling to the tumor cell per se, but rather, the actual attack of, or the actual destruction of the tumor cells which induces the upregulation of PD-L1 on their cell surface.

If it had to do with signaling, then LL might have another MOA, but I tend to think that it is the actual attack and subsequent destruction which is actually the cause of the upregulation.

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The rise in inflammatory M1 macrophages is a response to insults to the body (viral, bacterial, injury, tumors, genetic aberrations). They are M1 macrophages because of the inflammatory cytokines that are expressed on them that cause the macrophages to attack invaders or in the case of injury, tumors and genetic aberrations the body's own cells that are either dying or seen as different from normal.

Let's look at cancer as an example. When cancer develops the immune system will see the tumor cells as other start increasing killer immune cells (M1 macrophages) in response. Those M1 macrophages see specific regions of the cancer cell (antigens) to target and develop antibodies on M1 macrophages that can bind to the antigens and destroy the tumor cells. The problem arises when there are highly excessive M1 macrophages that can go on to destroy normal cells. The high M1 (inflammatory) cytokine levels themselves trigger a switch to M2 (anti-inflammatory) cytokines to keep the immune system in homeostasis and limit normal cell destruction. Where problems arise is that often homeostasis is not achieved and an imbalance between M1 and M2 lead to a wide variety of other disease states.

Leronlimab's switch to an M1 macrophage level might initially lead to an increase in M2 cytokine levels (PD-L1, IL-4, IL-10, IL-13, TGF-b etc.). But that's where CCL5 (RANTES) would come into play. CCL5 highly preferentially binds to CCR5 over binding to CCR1, CCR3 and CCR4. CCL5 induces the migration of macrophages to sites of bodily insult. With any insult you would see an increase in CCR1, CCR3, CCR4 and CCR5, but CCR1, CCR3 and CCR4 are far less numerous than CCR5. The result would be a closer to normal M1 and M2 response at the site of bodily insult leading to the ability of M1 macrophages to more effectively destroy the tumor when anti-inflammatory cytokines such as PD-L1 are controlled.

The lowering of PD-L1 after 90 days may be due to less tumor burden due to tumor cell degradation or death or possibly partial macrophage exhaustion.