PMN-MDSC and arginase are increased in myeloma and may contribute to resistance to therapy

Objectives: Despite improvement in overall response due to the introduction of the first-in-class proteasome inhibitor bortezomib (btz), multiple myeloma (MM) is still an incurable disease due to the immune-suppressive bone marrow (BM) environment. Thus, the authors aimed to identify the role of CD11b+CD15+CD14−HLA-DR− granulocytic-like myeloid-derived suppressor cells (PMN-MDSC) in MM patients treated up-front with novel agents. Methods: In MM cell lines and primary cells derived by patients affected by MGUS and MM, we investigated sensitivity to bortezomib and lenalidomide in presence of Arg-1 and PMN-MDSC. Results: The authors found that PMN-MDSC and their function through increased arginase-1 (Arg-1) are associated with MM progression. When the authors assessed cell viability of the human myeloma cell lines MM1.s, OPM2 and U266 treated with 5–20 nM btz for 24 h in PMN-MDSC conditioned media, they disclosed that amount of Arg-1 and Arg-1 inhibition could affect btz sensitivity in-vitro. PMN-MDSC and Arg-1 were increased in peripheral blood of newly diagnosed MM patients compared to healthy subjects. PMN-MDSC and arginase were reduced after exposure to lenalidomide-based regimen but increased after btz-based treatment. Conclusion: In MM, Arg-1 is mainly expressed by PMN-MDSC. PMN-MDSC and Arg-1 are reduced in vivo after lenalidomide but not bortezomib treatment.研究目的：尽管首创类蛋白酶体抑制剂硼替佐米（bortezomib，btz）的问世使总体应答率得到改善，但多发性骨髓瘤（multiple myeloma，MM）仍因免疫抑制性骨髓（bone marrow，BM）微环境而无法治愈。因此，本研究旨在明确CD11b+CD15+CD14−HLA-DR−粒细胞样髓系来源抑制细胞（polymorphonuclear myeloid-derived suppressor cells，PMN-MDSC）在接受新型药物一线治疗的MM患者中的作用。 研究方法：本研究针对MM细胞系以及意义未明单克隆免疫球蛋白血症（monoclonal gammopathy of undetermined significance，MGUS）和MM患者来源的原代细胞，探究了在精氨酸酶-1（arginase-1，Arg-1）与PMN-MDSC存在的情况下，细胞对硼替佐米和来那度胺的敏感性。 研究结果：本研究发现，PMN-MDSC及其通过上调精氨酸酶-1（Arg-1）所介导的功能与MM疾病进展相关。当研究者将人骨髓瘤细胞系MM1.s、OPM2及U266置于PMN-MDSC条件培养基中，用5~20 nM的硼替佐米处理24小时后评估细胞活力时，证实Arg-1的表达水平及Arg-1抑制作用可在体外影响硼替佐米的敏感性。与健康受试者相比，初诊MM患者外周血中的PMN-MDSC及Arg-1水平均升高。采用基于来那度胺的治疗方案后，PMN-MDSC与精氨酸酶水平均有所降低；而采用基于硼替佐米的治疗方案后，二者水平则升高。 研究结论：在MM中，Arg-1主要由PMN-MDSC表达。接受来那度胺治疗后，体内PMN-MDSC及Arg-1水平降低，但硼替佐米治疗并未产生此类变化。