Immune cell microenvironment is a critical component regulating myeloma progression and efficacy of various immunotherapies. Myeloma grows in complex foci or clusters within the bone marrow, and the composition and organization of these structures is poorly understood. Interestingly, we have found non-malignant long lived plasma cells also form dynamic clusters in the bone marrow suggesting a common survival niches. In patients, analyses of myeloma tumor microenvironment (TME) typically rely on imprecise bone marrow aspirates, which can collect random samplings of the marrow parenchyma as well as peripheral blood, and may contain variable and unknown proportion of myeloma foci or the relevant TME. To precisely profile immune microenvironment precisely within myeloma foci, we inoculated photoactivatable-GFP (PA-GFP) expressing immunocompetent mice with Vk*MYC GFP cells, and using two-photon microscopy in the tibia, we photo-labeled immune cells within the foci and analyzed by flow. We discovered the composition within foci was distinct compared to bulk bone marrow within the same marrow, which mimicked naïve marrow composition, suggesting unique TME were limited to myeloma foci volume. We also conducted longitudinal bulk analyses of total BM with tumor growth and found that distinct changes in myeloid cell composition with tumor burden, suggesting multiple phases in TME evolution. Finally, using genetic ablation of myeloid cells using DTR expressing mice, we found that macrophage and monocytes promoted tumor spreading to other bones, while plasmacytoid dendritic cells suppressed spreading. These findings highlight the dynamics and precision of the myeloma TME and how it regulates tumor progression.
No relevant conflicts of interest to declare.
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