Immunoregulatory roles of versican proteolysis in the myeloma microenvironment

Abstract

• Interplay between myeloma niche stromal cells and myeloid cells generates versikine, a novel damageassociated molecular pattern.• Versikine may promote antigen-presenting cell maturation and CD8 1 T-cell activation/recruitment to the tumor bed.Myeloma immunosurveillance remains incompletely understood. We have demonstrated proteolytic processing of the matrix proteoglycan, versican (VCAN), in myeloma tumors. Whereas intact VCAN exerts tolerogenic activities through Toll-like receptor 2 (TLR2) binding, the immunoregulatory consequences of VCAN proteolysis remain unknown. Here we show that human myeloma tumors displaying CD81 infiltration/aggregates underwent VCAN proteolysis at a site predicted to generate a glycosaminoglycan-bereft N-terminal fragment, versikine. Myeloma-associated macrophages (MAMs), rather than tumor cells, chiefly produced V1-VCAN, the precursor to versikine, whereas stromal cell-derived ADAMTS1 was the most robustly expressed VCAN-degrading protease. Purified versikine induced early expression of inflammatory cytokines interleukin 1b (IL-1b) and IL-6 by human myeloma marrow-derived MAMs. We show that versikine signals through pathways both dependent and independent of Tpl2 kinase, a key regulator of nuclear factor kB1-mediated MAPK activation in macrophages. Unlike intact VCAN, versikine-induced Il-6 production was partially independent of Tlr2. In a model of macrophage-myeloma cell crosstalk, versikine induced components of "T-cell inflammation," including IRF8-dependent type I interferon transcriptional signatures and T-cell chemoattractant CCL2. Thus the interplay between stromal cells and myeloid cells in the myeloma microenvironment generates versikine, a novel bioactive damage-associated molecular pattern that may facilitate immune sensing of myeloma tumors and modulate the tolerogenic consequences of intact VCAN accumulation. Therapeutic versikine administration may potentiate T-cell-activating immunotherapies. (Blood. 2016;128(5):680-685)

Versican-Derived Matrikines Regulate Batf3–Dendritic Cell Differentiation and Promote T Cell Infiltration in Colorectal Cancer

“…VCAN contributes to cancerous and non-cancerous inflammation by promoting leukocyte-derived elaboration of inflammatory mediators (8–13) but also immunodeficiency through dendritic cell (DC) dysfunction (14). Interestingly, we also detected in situ VCAN proteolysis in a pattern consistent with the activities of a-disintegrin-and-metalloproteinase-with-thrombospondin-motifs (ADAMTS) proteases (15). We hypothesized that VCAN proteolysis serves to generate bioactive fragments (“matrikines”)(16–18).…”

“…We hypothesized that VCAN proteolysis serves to generate bioactive fragments (“matrikines”)(16–18). Indeed, we demonstrated a fragment containing VCAN’s N-terminal 441 amino acids, “versikine” (19), elicits a transcriptional program that is predicted to promote immunogenicity, and thus, antagonize the tolerogenic actions of its parent, intact VCAN (15). However, it is unclear whether VCAN-dependent immunoregulatory mechanisms are operative in non-myeloma, or indeed non-hematopoietic, settings.…”

Provisional matrix: A role for versican and hyaluronan

“…In addition, hyaluronan fragments can be pro-inflammatory by stimulating inflammatory cytokine release by myeloid cells [165, 166]. The bioactive members of the ADAMTS family of proteases can degrade versican to form versican fragments such as versikine [167] which can be pro-apoptotic in some systems [52] and/or immunoregulatory [168] in other systems. Furthermore, fragments of hyaluronan promote collagen production in some cells [140].…”

“…In fact, we found that incubating versican with hyaluronan before adding to activated T lymphocytes inhibited the binding of hyaluronan to the lymphocytes and blocked the migration of T lymphocytes [155]. In addition, versican and versican fragments, like hyaluronan fragments , can bind TLR2 and 4 and induce inflammatory cytokine release from monocytes/macrophages [168, 184–192] providing yet another example of how ECM components possess bioactivity and regulate critical events during the early inflammatory response.…”

Towards integrating extracellular matrix and immunological pathways

“…Degradation of versican by ADAMTS enzymes during development of mice induces apoptosis in the interdigital tissue and promotes proper limb formation (106). Recently, versican proteolysis and production of the matrikine versikine was found to induce production of the inflammatory cytokines IL-6 and IL-1β in the myeloma microenvironment (107). Given the large number of proteoglycans and glycoproteins that can be present in the ECM in various tissues, there are almost certainly additional matrikines that play important roles in other biological functions that have yet to be identified.…”