Immune-mediated tumor control in the 5TGM1 transfer model of multiple myeloma

Abstract

Multiple myeloma is a disease of malignant plasma cells residing in the bone marrow, where interactions with local immune cells are thought to contribute to disease pathobiology. However, since a multiple myeloma diagnosis is virtually always preceded by an asymptomatic precursor phase, identifying early alterations in the bone marrow micro-environment following occupation by multiple myeloma cells remains challenging. Here we used the 5TGM1 transfer model of murine myeloma in combination with myeloma-permissive KaLwRij mice and myeloma-resistant C57Bl/6 mice and hypothesized that differential sensitivity to myeloma in these HLA-identical mouse strains has an immunological basis and might allow for dissection of early immune responses to myeloma cells. Using flow cytometry and single-cell RNA sequencing we show that C57Bl/6 mice can restrain tumor growth for prolonged periods, associated with activation of cytotoxic immune responses that were absent from KaLwRij mice. Transcriptional analysis of immune cells and stromal cells identified a central role for IFN-signaling in tumor containment, and antibody-mediated neutralization of IFNγ increased both incidence and outgrowth of multiple myeloma in C57Bl/6 mice. Together these findings highlight the ability of a fully functional immune system to control multiple myeloma progression in an IFNγ-dependent manner and suggest that transfer of 5TGM1 cells into parental C57Bl/6 mice can serve as a faithful model to track anti-myeloma immune responses in immune competent and genetically modifiable mice.

Transcriptional Remodeling of the Stromal and Endothelial Microenvironment in MGUS to Multiple Myeloma Progression

“…Notably, we observed that this MM-IFN signature is not exclusive to EC, but also extends to MSC, suggesting a shared response of the BM microenvironment during myeloma progression. While the IFN-related signature has previously been reported in PC and the immune environment 14,15,50 , our data reveal that, in fact, non-hematopoietic cells also exhibit the IFN fingerprint. This IFN-related signature is marked by the upregulation of IFN-inducible genes and involved master regulators such as Irf7, Stat1, and Stat2.…”

“…A fundamental finding of our study is the identification of a myeloma-specific IFN signature in EC that extends to MSC and other BM populations, suggesting a shared response of the BME during myeloma progression. While IFN-related signature has been reported in PC and the immune environment 4,5,46 , our data reveal that, in fact, non-hematopoietic cells exhibit this IFN fingerprint marked by the upregulation of IFN-inducible genes and the master regulators Irf7, Stat1, and Stat2. Previous studies highlighted STAT3 as an oncogenic driver in MM and reported the role of STAT1 in promoting MM migration and BM homing 47 .…”