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.
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 humanmyeloma 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.
Authors: Chunhua Fu; Yuanqing Lu; Mason A Williams; Mark L Brantly; Corey E Ventetuolo; Laurence M Morel; Borna Mehrad; Edward W Scott; Andrew J Bryant Journal: Br J Pharmacol Date: 2020-02-04 Impact factor: 9.473