TPL2 kinase regulates the inflammatory milieu of the myeloma niche

Abstract

Key Points We describe a novel, druggable pathway that controls myeloma growth through macrophages in the myeloma microenvironment. Macrophages are dominant orchestrators of the inflammatory milieu of the myeloma niche.

Versican vs versikine: tolerance vs attack

“…4,5 The delicate maintenance of platelet homeostasis has initially been explained by the "autoregulation" model, which postulates that TPO is produced at a constant rate and cleared by binding to TPO receptors on platelets followed by internalization and degradation. 6 However, a growing body of evidence suggests the presence of other regulatory mechanisms in TPO production. Recently, the hepatic Ashwell-Morrell receptor (AMR) was shown to mediate the removal of desialylated platelets and regulate hepatic TPO synthesis, providing a better understanding of the transcriptional regulation of TPO production 7,8 (see figure).…”

“…Hope et al have previously described the effect of macrophages on myeloma cells and demonstrated the regulation of the inflammatory milieu in the myeloma niche through the tumor progression locus 2 (TPL2) kinase. 6 In their work in the present issue, the group investigated the proteolysis of the matrix proteoglycan versican which is abundantly produced by myeloma-associated macrophages (MAMs). Versican itself causes tolerogenic polarization of APCs through the Toll-like receptor (TLR2).…”

Deploying myeloid cells against myeloma

“…We have previously reported that myeloma-associated monocytes/macrophages (MAM) actively synthesize IL-6, IL-10 and IL-1b 4 . Because the myeloma microenvironment is essentially IL-4-free, we hypothesized that MAM may resemble "regulatory macrophages (M2b)," rather than the prototypical IL-4-educated M2a macrophages.…”

“…We recently showed that the TLR2/6 ligand matrix proteoglycan, versican, is abundant in myeloma lesions and may play a role in this process. 4 Alternatively, macrophages may acquire a regulatory phenotype through interaction with mesenchymal stem/stromal cells (MSC). 6 Reprogramming tumor-promoting MAM into tumorsuppressive MAM Reprogramming M2b tumor-promoting macrophages into tumor-suppressive M1 macrophages may result in tumor regression or eradication.…”

“…Because the myeloma microenvironment is essentially IL-4-free, we hypothesized that MAM may resemble "regulatory macrophages (M2b)," rather than the prototypical IL-4-educated M2a macrophages. 4 M2b macrophages are M2 macrophages characterized by production of immunomodulatory cytokines IL-10, IL-1b, IL-6 and TNFa 5 with suppression of IL-12. By contrast, "classically-activated" M1 macrophages produce high IL-12 and low IL-10 with variable amounts of IL1b, IL-6 and TNFa.…”