Extracellular matrix and the myeloid-in-myeloma compartment: balancing tolerogenic and immunogenic inflammation in the myeloma niche

Abstract

The last 10-15 years have witnessed a revolution in treating multiple myeloma, an incurable cancer of Ab-producing plasma cells. Advances in myeloma therapy were ushered in by novel agents that remodel the myeloma immune microenvironment. The first generation of novel agents included immunomodulatory drugs (thalidomide analogs) and proteasome inhibitors that target crucial pathways that regulate immunity and inflammation, such as NF-κB. This paradigm continued with the recent regulatory approval of mAbs (elotuzumab, daratumumab) that impact both tumor cells and associated immune cells. Moreover, recent clinical data support checkpoint inhibition immunotherapy in myeloma. With the success of these agents has come the growing realization that the myeloid infiltrate in myeloma lesions-what we collectively call the myeloid-in-myeloma compartment-variably sustains or deters tumor cells by shaping the inflammatory milieu of the myeloma niche and by promoting or antagonizing immune-modulating therapies. The myeloid-in-myeloma compartment includes myeloma-associated macrophages and granulocytes, dendritic cells, and myeloid-derived-suppressor cells. These cell types reflect variable states of differentiation and activation of tumor-infiltrating cells derived from resident myeloid progenitors in the bone marrow-the canonical myeloma niche-or myeloid cells that seed both canonical and extramedullary, noncanonical niches. Myeloma-infiltrating myeloid cells engage in crosstalk with extracellular matrix components, stromal cells, and tumor cells. This complex regulation determines the composition, activation state, and maturation of the myeloid-in-myeloma compartment as well as the balance between immunogenic and tolerogenic inflammation in the niche. Redressing this balance may be a crucial determinant for the success of antimyeloma immunotherapies.

Early alterations in stem-like/marrow-resident T cells and innate and myeloid cells in preneoplastic gammopathy

“…The altered phenotype of tumor-infiltrating myeloid cells, including reduced expression of CD86, CD155, and c-KIT and increased PD-L1, supports an immune-suppressive phenotype. These data, therefore, support prior studies showing enrichment of myeloid cells in MM, including their protumor effects (18). Reduced expression of Fas in MM myeloid cells is of interest because Fas/FasL interactions play a major role in regulating myeloid cell kinetics, as illustrated by increased myeloid progenitors in mice with mutated Fas/FasL (29), and may contribute to their enrichment in MM.…”

“…Analysis of differentially expressed genes within myeloid clusters revealed reduced transcripts of HLA-DR in MM, consistent with a less activated phenotype and consistent with the mass cytometry data showing lower CD86 as a marker of reduced activation in MM myeloid cells ( Figure 4C). Genes increased in MM myeloid cells also included several genes with possible implications for immunosuppressive properties (such as IL1R2 and calcium-binding proteins S100A8, S100A9, and S100A12), as well as other genes (e.g., versican) previously implicated in this role (18). GSEA of differentially expressed genes identified dendritic cell (DC) activation as a pathway altered in these cells, supporting a role for altered antigen presentation (Supplemental Figure 8).…”

The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer

“…Solid tumors are more than just a lump of cancer cells. Beside stromal cells, non-cellular components of the TM include the ECM and soluble growth factors [ 93 , 94 , 95 , 96 , 97 , 98 ]. The interaction between cells and their respective microenvironment is key for cellular growth and the maintenance of homeostasis.…”

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

“…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). 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).…”