“IFN-γ Upregulation: Increased T-cell/NK-cell a

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“IFN-γ Upregulation: Increased T-cell/NK-cell activity in the TME likely boosts IFN-γ secretion. IFN-γ is a key driver of PD-L1 expression via the JAK/STAT pathway, as it activates transcription factors (e.g., IRF1) that bind the PD-L1 promoter.“

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Another mystery to add to what is happening with PD-L1.

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Leronlimab, mAb to CCR5, Trims Liver Fat in 14-Week Trial of NASH Patients

Compared with participants receiving placebo, those getting 350 mg of leronlimab weekly also had significant drops in ALT, AST, alkaline phosphatase and multiple markers of inflammation: VCAM, CCL2, CCL3, CCL5, CCL18, interferon gamma , IL-6, IL-8, IL-1 receptor antagonist. TNF receptor 2, and tissue inhibitor of MMP-1 and EN RAGE.

NASH01 investigators suggested leronlimab controls inflammation via multiple mechanisms involving VCAM, CCL2, CCL3, CCL11, and CCL18. Competitive binding of leronlimab to CCR5 may also contribute to antiinflammatory activity, they proposed.

https://www.natap.org/2022/EASL/EASL_70.htm

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Interferon gamma is also known as IFN-y. Is there another chemokine that leronlimab does not control that is driving PD-L1 expression? Possibly IFN-y is increasing only around tumors, CTCs and CAMLs where there is a heavier macrophage accumulation and not where the disease is primarily inflammatory with little macrophage accumulation. Maraviroc has not been successful enough in cancer for them to pursue it further. The lesser CCR5 binding by maraviroc might not induce a heavy macrophage accumulation.