Versican vs versikine: tolerance vs attack

In this issue of Blood, Hope et al demonstrate the differential influence of versican and its proteolytic derivate, versikine, on the immune system. This discovery opens a new avenue for immunotherapies in multiple myeloma patients.¹ 

Multiple myeloma is an (oligo)clonal plasma cell disease which can develop in the bone marrow and also, in some cases, as extramedullary disease in soft tissue. Tumor escape mechanisms in multiple myeloma still need to be identified. The graft-versus-myeloma effect observed after allogeneic stem cell transplantation clearly demonstrates that T lymphocyte can play a role in the antitumor defense of the immune system. In the last 2 decades, several tumor-associated antigens (TAAs) with therapeutic relevance have been defined.²  Such TAA-specific T cells can be elicited and augmented, for example, by vaccination with tumor antigen-derived peptides.³  These antimyeloma T-cell responses may be hampered by standard drugs used in myeloma therapy like steroids (prednisone, dexamethasone) which have a potent antiproliferative action. In modern myeloma therapy, thalidomide and its derivatives play a crucial role. These immunomodulatory drugs are not only antiproliferative agents, but they also exert effects on antigen-presenting cells (APCs) and T cells, thus modulating and enhancing or suppressing TAA-directed T-cell responses.⁴ 

Immunotherapy, with breakthrough potential, has also reached myeloma therapy: treatment of myeloma with monoclonal antibodies against signaling lymphocytic activation molecule F7 (SLAMF7; also called CS1) and CD38 has been approved by regulatory authorities.⁵ 

Therapeutic approaches using the innate immune system, like natural killer cells and TAA-specific T-cell approaches with chimeric antigen receptors (CARs),²  are being investigated clinically. Therefore, there is a fervent need for a better understanding of the interaction of the myeloma niche with the immune system to further improve immunotherapies for myeloma patients.

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).⁷  Mesenchymal stromal cell–derived protease ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) cleaves the Glu⁴⁴¹-Ala⁴⁴² from versican, creating a molecule called versikine (see figure). Versikine induces proinflammatory IL-6 which is partially independent of TLR2 and does not interfere with expression of IL-1β. Versikine induces IL-12p40 through bone marrow–derived macrophages. The action is signaled through the MAP3K Tpl2. T cells are attracted to the myeloma niche by chemotactic mediators like CCL2. Like IL-27, versikine can upregulate interferon regulatory factor 8 on tumor cells which makes them prone to apoptosis. Using immunohistochemistry, Hope et al could demonstrate that, in case of high versikine expression with the neoepitope DPEAAE, a high frequency of CD8⁺ T cells could also be observed in the respective tissue. The interaction of macrophages and T cells creates a type I cytokine inflammatory milieu which enhances T-cell (and likely also innate) immune responses against myeloma cells. Therefore, versikine creates a novel bioactive DAMP stimulating an antimyeloma response by the immune system.

Versikine will be tested as an adjuvant in future trials with T-cell epitope peptide vaccination, CAR, and other T-cell therapies.