CSF1R-Inhibition and Reduction of Macrophages Delays Multiple Myeloma Growth in a Non-T-Cell-Dependent Manner

Macrophages are important tumor-promoting cells, and can constitute up to half of the tumor mass, orchestrating remodeling, inducing angiogenesis and suppressing the immune system to terminate local inflammatory responses. Colony stimulating factor (CSF-1), also known as macrophage colony-stimulating factor (M-CSF), is the most important cytokine involved in survival, proliferation and differentiation of tissue macrophages and their precursors. Previous experiments from our group has shown that amount of CSF-1 in the tumor bed correlates with successful rejection of cancer cells in a TCR-transgenic model where CD4⁺ T cells recognize a tumor specific antigen produced by multiple myeloma cells. We therefore tested if reduced signaling via CSF-1R, and thereby a decrease in tumor infiltrating macrophages, would results in decreased growth of multiple myeloma cells. .

PLX3397, a tyrosine kinase inhibitor with specificity for CSF1R and KIT, has been demonstrated to delay tumor growth in a CD8⁺ T-cell-dependent manner after chemotherapeutic treatment in a murine model of mammary carcinogenesis. Here, we show that MOPC315 multiple myeloma cells implanted subcutaneously in matrigel plugs in SCID mice become infiltrated with M2 phenotype macrophages that enhances their growth. When given chow containing PLX3397, recruitment of macrophages is strikingly reduced, with significant delay in tumor growth. Importantly, this delay in tumor development is not T cell dependent, since the anti-tumor effect is seen in T cell deficient SCID-mice as well as in BALB/c mice. Importantly, treatment with PLX3397 does not abrogate efficient tumor killing, and does not affect survival, when tested in a TCR-transgenic model where CD4⁺ T cells via induction of M1 macrophages reject multiple myeloma.

In conclusion, PLX3397 delays tumor growth by reducing amounts of tumor infiltrating M2 macrophages, while rendering effective tumor killing by M1 macrophages uninhibited. Thus, drugs that inhibit signaling of CSF-1 could be of value in treatment of multiple myeloma.