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Multiple myeloma induces the immunosuppressive capacity of distinct myeloid-derived suppressor cell subpopulations in the bone marrow

Leukemia volume 26, pages 2424–2428 (2012)Cite this article

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Multiple myeloma (MM) is a plasma cell neoplasm localized in the bone marrow (BM). Autologous stem cell transplantation and novel agents, like proteasome inihibitors (Velcade) and immunomodulatory agents (thalidomide and lenalidomide), have significantly improved the treatment of MM patients.1 However, this type of cancer still remains incurable. T-lymphocyte-mediated immunotherapy has been considered as a potential new avenue for the treatment of MM, based on the observations that MM cells can be recognized and lysed by CD4+ and CD8+ cytotoxic T cells.2 However, dysfunction of immune cells (T cells, dendritic cells, B cells) and an immunosuppressive BM microenvironment are described in MM patients, although the mechanisms governing this immunosuppression are not well characterized.3, 4 Revealing the mechanisms of immunodeficiency in MM patients could lead to a better understanding of MM progression and pathogenesis, and to the development of improved therapies including immunotherapy. A possible mechanism of immunosuppression, which has not been reported yet in MM, is the inhibition of T-cell activity by myeloid-derived suppressor cells (MDSCs). MDSCs are a heterogeneous mixture of myeloid cells in different maturation stages that expand in the blood and lymphoid organs of tumor-bearing animals and cancer patients.5, 6 In mice, MDSCs are defined as CD11b+ Gr-1+ cells, whereas in humans, they are defined as Lin−HLA-DR−/low CD11b+CD33+ cells with variable expression of CD14, CD15 and selected other markers.7 Recent reports have shown the existence of subtypes of MDSCs with distinct phenotype, morphology and, importantly, distinct immunosuppressive mechanisms. The bulk CD11b+Gr−1+ MDSC population in mice can be further subdivided in a Ly6G− mononuclear fraction and a Ly6G+ polymorphonuclear fraction.6 Most of our current knowledge on MDSCs is obtained by studying solid tumors that expand MDSCs in the lymphoid organs, but information on whether cancer cells residing in the BM are able to directly influence MDSC generation in situ is lacking. In this study, we investigated the phenotype, immunosuppressive activity and mechanism of BM MDSC subsets in the syngeneic 5TMM mouse models (5T2MM and 5T33MM).8 These models are well characterized and closely resemble the human disease. Importantly, the MM cells grow in the BM in fully immunocompetent mice, allowing the study of MDSCs in a relevant in vivo setting. Two subsets of 5T33MM tumor bearers can be identified: ‘5T33MM high’ mice have a high tumor load in the BM (more than 50% cancer cells and typically less than 30% CD11b+ cells in BM), whereas ‘5T33MM low’ have a lower tumor load in the BM (less than 40% cancer cells and more than 50% CD11b+ cells).

Various mechanisms through which MDSC can suppress T-cell proliferation have been reported, including the production of reactive-oxygen species by the NADPH oxidase complex10 or the concerted action of inducible nitric oxide synthase (iNOS) and arginase,11 the production of NO by iNOS6 and the depletion of L-arginine by arginase.12 The higher immunosuppressive activity of myeloma-derived MDSCs compared with normal MDSCs is accompanied by a higher gene expression of iNOS, arginase-1 and interleukin-10 (Supplementary Figure 1). In addition, production of NO by the 5T33MM Ly6Glow cells is consistently higher than naive cells (Figure 1f). NADPH oxidase component gp91phox and COX-2 (generating increased levels of reactive-oxygen species and prostaglandin E2, respectively), and inflammatory cytokines such as interleukin-12p40, interleukin-1β and tumor necrosis factor are not induced in 5TMM-stimulated MDSC subsets compared with naive MDSCs (Supplementary Figure 1). These data illustrate the specific induction of particular genes, with a potential implication in T-cell suppression, in both CD11bhighLy6Glow and CD11bhighLy6Ghigh BM cells by MM. To unravel the suppressive mechanism of BM MDSC subsets of MM-diseased mice, specific inhibitors of each pathway were used in ovalbumin-stimulated OT-1/5TMM MDSC cocultures. 5T33MM Ly6Glow-mediated suppression was partially, but significantly, reversed by the iNOS inhibitor L-NMMA, whereas the arginase inhibitor norNOHA had no effect, either alone or in combination with L-NMMA (Figure 1g). Furthermore, the COX-2 inhibitor sc-791 tended to lower suppression, whereas the reactive-oxygen species-scavenging enzymes SOD and catalase even slightly enhance suppression (Figure 1g). To assess the kinetics of MDSC induction by MM, we investigated the immunosuppressive capacity of 5T2MM Ly6Glow and Ly6Ghigh subsets at different time points of disease progression (3, 6, 9, 12 weeks). An increased T-cell suppressive capacity of 5T2MM MDSC subsets could already be observed after 3 weeks (Supplementary Figure 2)—a time point at which the tumor load is very low—and was maintained throughout weeks 6, 9 and 12 (data not shown), indicating that this is an early event in MM disease. Importantly, already at the very early time point, the 5T2MM Ly6Glow-mediated suppressive mechanism depends on NO and is enhanced by SOD and catalase (Supplementary Figure 2). Finally, none of the tested inhibitors/scavengers is able to reverse the suppression by Ly6Ghigh BM cells from 5T33MM-diseased or 5T2MM-diseased mice (data not shown).

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Acknowledgements

We would like to thank Angelo Willems and Carine Seynaeve for their expert technical assistance. The work was financially supported by the International Myeloma Foundation, Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO-Vl), Stichting tegen Kanker, King Baudouin Foundation, Multiple Myeloma Research Foundation, the European Stem cell network (EUFP6 MSCNET) and the Onderzoeksraad Vrije Universiteit Brussel (GOA48, OZR-VUB). E Van Valckenborgh, E Menu and E De Bruyne are postdoctoral fellows, and E Schouppe and K Movahedi are predoctoral fellows of FWO-Vl. JA Van Ginderachter is supported by Stichting tegen Kanker. OT-1 mice were a kind gift of Dr Muriel Moser (ULB, Brussels, Belgium). Non-labeled anti-CCR2 (MC-21) was a gift of Dr Matthias Mack (University of Regensburg, Germany).

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  1. K Vanderkerken and J A Van Ginderachter: These authors should be considered as senior author.

Authors and Affiliations

  1. Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium

    E Van Valckenborgh, E De Bruyne, E Menu & K Vanderkerken

  2. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium

    E Schouppe, K Movahedi, P De Baetselier & J A Van Ginderachter

  3. Myeloid Cell Immunology Laboratory, VIB, Brussels, Belgium

    E Schouppe, K Movahedi, P De Baetselier & J A Van Ginderachter

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Van Valckenborgh, E., Schouppe, E., Movahedi, K. et al. Multiple myeloma induces the immunosuppressive capacity of distinct myeloid-derived suppressor cell subpopulations in the bone marrow. Leukemia 26, 2424–2428 (2012). https://doi.org/10.1038/leu.2012.113

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