Tumor matrix remodeling in anti-myeloma immunity and immunotherapy

PROJECT SUMMARY/ ABSTRACT
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.

Grant Number: 7R01CA252937-06
NIH Institute/Center: NIH
Principal Investigator: Fotios Asimakopoulos