Tumour-associated macrophage-mediated survival of myeloma cells through STAT3 activation

Overcoming drug resistance is one of the greatest challenges in the treatment of multiple myeloma (MM). The interaction of myeloma cells with the bone marrow (BM) micro-environment is a major contributing factor to drug resistance. Tumor-associated macrophages or TAMs with different polarization states are an important component of this micro-environment. Previous studies revealed a role of TAMs in MM survival and drug resistance; however, the impact of macrophage polarization (anti-tumoral "M1" versus pro-tumoral "M2"-like phenotype) in this process is not yet described. Here the presence of TAMs was confirmed in MM patients on BM sections both at diagnosis and relapse using two M2 markers, CD163 and CD206. By following different TAM subpopulations during disease progression in the syngeneic murine 5T33MM model, we demonstrated a decrease in inflammatory monocytes and increase of M2-oriented TAMs in BM. Co-culture experiments demonstrated that macrophages induce a survival benefit to myeloma cells that is maintained after treatment with several classes of anti-myeloma agents (melphalan and bortezomib) and the biggest effect was observed with M2 polarized macrophages. The pro-survival effect was associated with an activation of the STAT3 pathway in 5T33MM cells, less cleavage of caspase-3 and thus less apoptosis. AZD1480, an ATP-competitive JAK2 inhibitor, abrogated the observed TAM mediated MM cell survival and partially inhibited resistance to bortezomib. Despite only a small quantitative impact on myeloid cells in vivo, AZD1480 treatment alone and in combination with bortezomib could significantly reduce tumor load. In conclusion, M2 TAMs are present in the MM micro-environment and contribute to MM cell survival and protection from drug-induced apoptosis. As a result of TAM-induced activation of the STAT3 pathway, 5T33MM cells are sensitized to AZD1480 treatment.