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

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. ### Competing Interest Statement Competing interests A.B. consults for BMS/Celgene, Janssen, Amgen and Sanofi. P.S. is on the advisory board for Amgen, BMS/Celgene, Janssen, Seagen and Pfizer and receives research support from Janssen, BMS/Celgene and Karyopharm.