Macrophages in multiple myeloma: emerging concepts and therapeutic implications

Abstract

Multiple myeloma, a clonal plasma cell malignancy, has long provided a prototypic model to study regulatory interactions between malignant cells and their microenvironment. Myeloma-associated macrophages have historically received limited scrutiny, but recent work points to central and non-redundant roles in myeloma niche homeostasis. The evidence supports a paradigm of complex, dynamic and often mutable interactions between macrophages and other cellular constituents of the niche. We and others have shown that macrophages support myeloma cell growth, viability and drug resistance through both contact-mediated and non-contact-mediated mechanisms. These tumor-beneficial roles have evolved in opposition to, or in parallel with, intrinsic pro-inflammatory and tumoricidal properties. Thus, simple blockade of protective "don't eat me" signals on the surface of myeloma cells leads to macrophage-mediated myeloma cell killing. Macrophages also enhance the tumor-supportive role of mesenchymal stem/stromal cells (MSCs) in the niche: importantly, this interaction is bidirectional, producing a distinct state of macrophage polarization that we termed "MSC-educated macrophages." The intriguing pattern of cross-talk between macrophages, MSCs and tumor cells highlights the myeloma niche as a dynamic multi-cellular structure. Targeted reprogramming of these interactions harbors significant untapped therapeutic potential, particularly in the setting of minimal residual disease, the main obstacle toward a cure.

Figure 1. Regulatory interactions between macrophages, mesenchymal stem/stromal cells (MSCs) and malignant plasma cells in the myeloma niche

Macrophages directly support malignant plasma cells through contact-mediated interactions, cytokine secretion and indirectly, through orchestration of the “angiogenic switch” and an immunosuppressive environment conducive for tumor cell propagation. These tumor-beneficial roles are balanced by inherent tumoricidal and phagocytic properties of activated macrophages. Myeloma-associated macrophages also engage in bidirectional interactions with mesenchymal stem/stromal cells (MSCs) and the latter, in turn, modulate the polarization state of macrophages (“MSC-educated macrophages”, see text) as well as provide direct support to tumor cells.

Figure 2. TPL2 kinase regulates myeloma growth through tumor cell-autonomous and non-autonomous mechanisms, the latter involving myeloma-associated macrophages

TPL2 is a key regulator of cytokine secretion by myeloma-associated macrophages. In malignant plasma cells, TPL2 activates downstream MAP kinases in response to growth and inflammatory signals. Targeted inhibition of TPL2 activity may disrupt crucial regulatory cross-talk between macrophages and malignant cells in the myeloma niche.