Multiple myeloma (MM) ranks as the second most common blood cancer and it remains incurable. Autologous stem cell transplantation (ASCT) remains a mainstay of therapy for eligible patients. Despite the routine use of novel agents as post-ASCT ?maintenance? to delay or prevent relapse, most patients will succumb after transplant. There is considerable body of evidence to suggest that immunoregulatory mechanisms established in post-ASCT bone marrow (BM) microenvironment favor relapse and constitute attractive therapeutic targets. Post-ASCT relapses depend on tolerogenic IL10-producing myeloid cells (dendritic cells (DC) and macrophages, collectively referred to as tol-DC) and IL17 proposed to act on MM cells in a cell-autonomous manner. However, the upstream signals or microenvironmental triggers that elicit these processes are unclear. Tol-DC polarization and Th17 differentiation are promoted through Toll-like receptor (TLR)-2 signaling. We previously reported that MM-accessory cells secrete the TLR2-ligand matrix proteoglycan, versican (VCAN). VCAN promotes tol-DC polarization in carcinomas and therefore, it constitutes a prime suspect for triggering relapse-promoting, TLR2-dependent processes in MM. In the MM microenvironment, specifically post-ASCT, VCAN undergoes ADAMTS-mediated extracellular proteolysis to release an N-terminal fragment, versikine. Versikine acts as a matrikine (an extracellular matrix- derived fragment that regulates cell activity, often in a manner distinct from that of its parent macromolecule). Versikine is a weak IL6/IL10 trigger, therefore it is unlikely to be a potent tol-DC/Th17 inducer. Instead, versikine stimulates IRF8-dependent transcripts and promotes the IRF8-dependent Batf3-DC subset in vitro and in vivo. We hypothesize that the versikine-IRF8-Batf3-DC axis may engage the potent (and perhaps dominant) tolerogenic VCAN-TLR2 pathway in a dynamic crosstalk. We have delineated 2 specific Aims to investigate the mechanisms by which VCAN and versikine regulate anti- MM immunity post-ASCT:
In Aim 1, we shall dissect VCAN-TLR2 signaling in anti-MM immunity and design novel post-ASCT treatment strategies based on targeting tolerogenic VCAN-TLR2 signaling.
In Aim 2, we shall study in-depth the role of the matrikine, versikine, in anti-MM immunity. Success of our Aims will optimize MM treatment (maintenance) strategies to prolong post-ASCT survival. The experiments proposed here are facilitated by our recent generation of the first Ras-driven MM model, VQ. RAS pathway is the most commonly mutated pathway in human MM. In contrast to current state-of-art MM models, VQ is readily transducible by lentiviral vectors and engrafts in C57BL/6J recipients (facilitating mechanistic in vivo studies). Several of the studies proposed here have been impossible or impractical using existing MM models.
Multiple myeloma (MM) is the second most common hematological malignancy. Despite the incorporation of novel agents in the autologous stem cell transplant (ASCT) backbone for MM treatment, MM remains incurable. In this application, we propose to target a novel immune regulatory pathway, the versican (VCAN) pathway, in order to optimize post-ASCT therapy for myeloma, and thus to prevent or delay relapses.
