bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2021-66-2-218-230bloodjour-283Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESМиелоидные супрессорные клетки периферической крови у больных множественной миеломой на этапе мобилизации гемопоэтических стволовых клетокMyeloidderived peripheral blood suppressor cells at haematopoietic stem cell mobilisation in multiple myeloma patientshttps://orcid.org/0000-0002-4885-8327АристоваТ. А.AristovaT. A.

Аристова Татьяна Андреевна, врач-гематолог гематологического отделения с блоком трансплантации костного мозга

630099, Новосибирск

Tatiana A. Aristova, Physician (haematology), Department of Haematology with Bone Marrow Transplantation Unit

630099, Novosibirsk

taris06@mail.ruhttps://orcid.org/0000-0003-2902-9336БаторовЕ. В.BatorovE. V.

Баторов Егор Васильевич, кандидат медицинских наук, научный сотрудник лаборатории клеточной иммунотерапии

630099, Новосибирск

Egor V. Batorov, Cand. Sci. (Med.), Researcher, Laboratory of Cell Immunotherapy

630099, Novosibirsk

Ebatorov@mail.ruhttps://orcid.org/0000-0003-1951-2260СергеевичеваВ. В.SergeevichevaV. V.

Сергеевичева Вера Васильевна, кандидат медицинских наук, заведующая гематологическим отделением с блоком трансплантации костного мозга

630099, Новосибирск

Vera V. Sergeevicheva, Cand. Sci. (Med.), Head of the Department of Haematology with Bone Marrow Transplantation Unit

630099, Novosibirsk

verden@bk.ruhttps://orcid.org/0000-0001-7109-3839СизиковаС. А.SizikovaS. A.

Сизикова Светлана Анатольевна, кандидат медицинских наук, врач-гематолог гематологического отделения с блоком трансплантации костного мозга

630099, Новосибирск

Svetlana A. Sizikova, Cand. Sci. (Med.), Physician (haematology), Department of Haematology with Bone Marrow Transplantation Unit

630099, Novosibirsk

svetlana_sizikova@mail.ruhttps://orcid.org/0000-0003-1822-6326УшаковаГ. Ю.UshakovaG. Yu.

Ушакова Галина Юрьевна, кандидат медицинских наук, врач-гематолог гематологического отделения с блоком трансплантации костного мозга

630099, Новосибирск

Galina Yu. Ushakova, Cand. Sci. (Med.), Physician (haematology), Department of Haematology with Bone Marrow Transplantation Unit

630099, Novosibirsk

bmt-novosibirsk@mail.ruhttps://orcid.org/0000-0002-0792-3110ГилевичА. В.GilevichA. V.

Гилевич Андрей Викторович, кандидат медицинских наук, заведующий отделением реанимации и интенсивной терапии

630099, Новосибирск

Andrey V. Gilevich, Cand. Sci. (Med.), Head of the Department of Resuscitation and Intensive Care

630099, Novosibirsk

agilevich@bk.ruhttps://orcid.org/0000-0001-8997-3586ШевелаЕ. Я.ShevelaE. Ya.

Шевела Екатерина Яковлевна, доктор медицинских наук, ведущий научный сотрудник лаборатории клеточной иммунотерапии

630099, Новосибирск

Ekaterina Ya. Shevela, Dr. Sci. (Med.), Leading Researcher, Laboratory of Cell Immunotherapy

630099, Novosibirsk

shevelak@mail.ruhttps://orcid.org/0000-0001-6895-938XОстанинА. А.OstaninA. A.

Останин Александр Анатольевич, доктор медицинских наук, профессор, главный научный сотрудник лаборатории клеточной иммунотерапии

630099, Новосибирск

Alexander A. Ostanin, Dr. Sci. (Med.), Professor, Chief Researcher, Laboratory of Cell Immunotherapy

630099, Novosibirsk

ostanin62@mail.ruhttps://orcid.org/0000-0003-2346-6279ЧерныхЕ. Р.ChernykhE. R.

Черных Елена Рэмовна, доктор медицинских наук, профессор, член-корреспондент РАН, заведующая лабораторией клеточной иммунотерапии

630099, Новосибирск

Elena R. Chernykh, Dr. Sci. (Med.), Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Cell Immunotherapy

630099, Novosibirsk

ct_lab@mail.ruФГБНУ «Научно-исследовательский институт фундаментальной и клинической иммунологии»РоссияResearch Institute of Fundamental and Clinical ImmunologyRussian Federation202101092021662218230Copyright © Аристова Т.А., Баторов Е.В., Сергеевичева В.В., Сизикова С.А., Ушакова Г.Ю., Гилевич А.В., Шевела Е.Я., Останин А.А., Черных Е.Р., 20212021Аристова Т.А., Баторов Е.В., Сергеевичева В.В., Сизикова С.А., Ушакова Г.Ю., Гилевич А.В., Шевела Е.Я., Останин А.А., Черных Е.Р.Aristova T.A., Batorov E.V., Sergeevicheva V.V., Sizikova S.A., Ushakova G.Y., Gilevich A.V., Shevela E.Y., Ostanin A.A., Chernykh E.R.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.htjournal.ru/jour/article/view/283Введение

Введение. Множественная миелома (ММ) представляет собой B-клеточную опухоль с  клональной экспансией плазматических клеток в  костном мозге. Высокодозная химиотерапия с  трансплантацией аутологичных гемопоэтических стволовых клеток является одним из  основных методов консолидирующей терапии больных множественной миеломой. Миелоидные супрессоры (МС)  — незрелые клетки миелоидного сопровождения, способные подавлять иммунный ответ. Введение гранулоцитарного колониестимулирующего фактора (Г-КСФ) с целью мобилизации гемопоэтических стволовых клеток (ГСК) вызывает увеличение количества МС в  периферической крови (ПК).

Цель  — изучить субпопуляции клеток, относящихся к  миелоидным супрессорам, в  периферической крови больных ММ в стадии ремиссии и изменение их численности на этапе мобилизации гемопоэтических стволовых клеток.

Методы

Методы. В исследование включено 35 больных ММ до и после курса мобилизации гемопоэтических стволовых клеток (ГСК). Количество гранулоцитарных МС (Г-МС, Lin–HLA-DR–CD33+ CD66b+ ), моноцитарных МС (М–МС, CD14+ HLA-DRlow/–) и МС ранних стадий дифференцировки (Lin–HLA-DR–CD33+ CD66b– ) оценивали методом проточной цитометрии.

Результаты

Результаты. Больные ММ в  стадии ремиссии отличались от  здоровых доноров более высоким процентным содержанием Г-МС (Lin–HLA-DR–CD33+ CD66b+ ) и повышенным относительным и абсолютным количеством М–МС (CD14+ HLA-DRlow/–). Численность М–МС существенно превышала количество Г-МС. Содержание субпопуляций МС было повышено как у  больных с  полным ответом (ПО) и  очень хорошим частичным ответом (ОХЧО), так и у больных с частичным ответом (ЧО). Более высокое относительное содержание Г-МС ассоциировалось с большей предлеченностью (2–3  линии химиотерапии). После мобилизации ГСК с  использованием циклофосфамида 2–4  г/м 2 + Г-КСФ (филграстим 5  мкг/кг/сутки) медианные значения относительного содержания Р-МС и  М–МС увеличивались, соответственно, в 2,3 и 2,0 раза, а относительное содержание Г-МС увеличивалось в 46 раз, что приводило к изменению баланса субпопуляций МС.

Заключение

Заключение. Больные ММ в  стадии ремиссии характеризовались повышенным процентным содержанием Г-МС и более высоким по сравнению с донорами содержанием М–МС (относительным и абсолютным). Большая предлеченность больных была ассоциирована с  более высокими показателями процентного содержания Г-МС. Степень ответа (ПО/ОХЧО против ЧО) не  была сопряжена с  различиями в  количественных показателях МС. Мобилизация ГСК препаратами Г-КСФ приводила к  значимому увеличению в  ПК всех трех анализируемых субпопуляций МС.

Introduction

Introduction. Multiple myeloma (MM) is a B-cell malignancy with clonal expansion of plasma cells in bone marrow. Highdose chemotherapy with autologous haematopoietic stem cell transplantation is among main consolidation therapies in MM. Myeloid-derived suppressor cells (MDSCs) are immature myeloid-accompanying cells able to suppress the immune response. The administration of granulocyte colony stimulating factor (G-CSF) to mobilise haematopoietic stem cells (HSCs) increases the MDSC count in peripheral blood (PB).

Aim — to study MDSC subsets in PB of remission MM patients and their incidence dynamics at HSC mobilisation.

Methods

Methods. The study surveyed 35 MM patients prior to and after HSC mobilisation. The counts of granulocytic (G-MDSCs; Lin–HLA-DR–CD33+ CD66b+), monocytic (М-MDSCs; CD14+ HLA-DRlow/–) and early MDSCs (E-MDSCs; Lin–HLA-DR– CD33+ CD66b–) were estimated in flow cytometry.

Results

Results. Remission MM patients differed from healthy donors in higher relative counts of G-MDSCs (Lin–HLA-DR– CD33+ CD66b+) and increased relative and absolute counts of М-MDSCs (CD14+ HLA-DRlow/–). М-MDSCs significantly outnumbered G-MDSCs. MDSC subset counts were elevated in complete response (CR) and very good partial response (VGPR), as well as in partial response (PR). Higher relative MDSC counts were associated with greater pretreatment (2–3 lines of chemotherapy). After HSC mobilisation with cyclophosphamide 2–4 g/m2 + G-CSF (filgrastim 5 μg/kg/day), the median relative E-MDSC and M-MDSC counts increased by 2.3 and 2.0 times, respectively, while the relative G-MDSC count raised 46-fold perturbing the MDSC subset balance.

Conclusion

Conclusion. Remission MM patients had the increased relative G-MDSC and both relative and absolute M-MDSC counts compared to donors. A greater patient pretreatment was associated with higher relative G-MDSC counts. Treatment response (CR/VGPR vs. PR) was not coupled with MDSC count variation. The G-CSF-induced HSC mobilisation entailed a significant expansion of all three MDSC subsets in PB.

множественная миеломасупрессорные клетки миелоидного происхождениямобилизация гемопоэтических стволовых клетокГ-КСФmultiple myelomamyeloid-derived suppressor cellshaematopoietic stem cell mobilisationG-CSFИсследование выполнено при финансовой поддержке РФФИ в рамках научного проекта № 20-15-00357 АResearch was supported by the Russian Foundation for Basic Research (grant 20-15-00357 a)ReferencesGabrilovich D.I. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017; 5(1): 3–8. DOI: 10.1158/2326-6066.CIR-16-0297.Gabrilovich D.I. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017; 5(1): 3–8. DOI: 10.1158/2326-6066.CIR-16-0297.Talmadge J.E., Gabrilovich D.I. History of myeloid-derived suppressor cells. Nat Rev Cancer. 2013; 13: 739–752. DOI: 10.1038/nrc3581.Talmadge J.E., Gabrilovich D.I. History of myeloid-derived suppressor cells. Nat Rev Cancer. 2013; 13: 739–752. DOI: 10.1038/nrc3581.Mandruzzato S., Brandau S., Britten C.M., et al. Toward harmonized phenotyping of human myeloid-derived suppressor cells by flow cytometry: results from an interim study. Cancer Immunol Immunother. 2016; 65: 161–169. DOI: 10.1007/s00262-015-1782-5.Mandruzzato S., Brandau S., Britten C.M., et al. Toward harmonized phenotyping of human myeloid-derived suppressor cells by flow cytometry: results from an interim study. Cancer Immunol Immunother. 2016; 65: 161–169. DOI: 10.1007/s00262-015-1782-5.Bronte V., Brandau S., Chen S.H., et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016; 7: 12150. DOI: 10.1038/ncomms12150.Bronte V., Brandau S., Chen S.H., et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016; 7: 12150. DOI: 10.1038/ncomms12150.Cubillos-Ruiz J.R., Mohamed E., Rodriguez P.C. Unfolding anti-tumor immunity: ER stress responses sculpt tolerogenic myeloid cells in cancer. J Immunother Cancer. 2017; 5: 5. DOI: 10.1186/s40425-016-0203-4.Cubillos-Ruiz J.R., Mohamed E., Rodriguez P.C. Unfolding anti-tumor immunity: ER stress responses sculpt tolerogenic myeloid cells in cancer. J Immunother Cancer. 2017; 5: 5. DOI: 10.1186/s40425-016-0203-4.Consonni F.M., Porta C., Marino A., et al. Myeloid-derived suppressor cells: Ductile targets in disease. Front Immunol. 2019; 10: 949. DOI: 10.3389/fimmu.2019.00949.Consonni F.M., Porta C., Marino A., et al. Myeloid-derived suppressor cells: Ductile targets in disease. Front Immunol. 2019; 10: 949. DOI: 10.3389/fimmu.2019.00949.Gabitass R.F., Annels N.E., Stocken D.D., et al. Elevated myeloid-derived suppressor cells in pancreatic esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother. 2011; 60: 1419–1430. DOI: 10/1007/s00262-011-1028-0.Gabitass R.F., Annels N.E., Stocken D.D., et al. Elevated myeloid-derived suppressor cells in pancreatic esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother. 2011; 60: 1419–1430. DOI: 10/1007/s00262-011-1028-0.Safarzadeh E., Orangi M., Mohammadi H., et al. Myeloid-derived suppressor cells: Important contributors to tumor progression and metastasis. J Cell Physiol. 2018; 233(4): 3024–3036. DOI: 10.1002/jcp.26075.Safarzadeh E., Orangi M., Mohammadi H., et al. Myeloid-derived suppressor cells: Important contributors to tumor progression and metastasis. J Cell Physiol. 2018; 233(4): 3024–3036. DOI: 10.1002/jcp.26075.Marvel D., Gabrilovich D.I. Myeloid-derived suppressor cells in the tumor microenvironment: Expect the unexpected. J Clin Invest. 2015; 125(9): 3356–3364. DOI: 10.1172/JCI80005.Marvel D., Gabrilovich D.I. Myeloid-derived suppressor cells in the tumor microenvironment: Expect the unexpected. J Clin Invest. 2015; 125(9): 3356–3364. DOI: 10.1172/JCI80005.Bruno A., Mortara L., Baci D., et al. Myeloid derived suppressor cells interactions with natural killer cells and pro-angiogenic activities: Roles in tumor progression. Front Immunol. 2019; 10: 771. DOI: 10.3389/fimmu.2019.00771.Bruno A., Mortara L., Baci D., et al. Myeloid derived suppressor cells interactions with natural killer cells and pro-angiogenic activities: Roles in tumor progression. Front Immunol. 2019; 10: 771. DOI: 10.3389/fimmu.2019.00771.Lv M., Wang K., Huang X.J. Myeloid-derived suppressor cells in hematological malignancies: Friends or foes. J Hematol Oncol. 2019; 12: 105. DOI: 10.1186/s13045-019-0797-3.Lv M., Wang K., Huang X.J. Myeloid-derived suppressor cells in hematological malignancies: Friends or foes. J Hematol Oncol. 2019; 12: 105. DOI: 10.1186/s13045-019-0797-3.Luyckx A., Schouppe E., Rutgeerts O., et al. G-CSF stem cell mobilization in human donors induces polymorphonuclear and mononuclear myeloid-derived suppressor cells. Clin Immunol. 2012; 143: 83–87.Luyckx A., Schouppe E., Rutgeerts O., et al. G-CSF stem cell mobilization in human donors induces polymorphonuclear and mononuclear myeloid-derived suppressor cells. Clin Immunol. 2012; 143: 83–87.Wang K., Lv M., Chang Y.J., et al. Early myeloid-derived suppressor cells (HLA-DR– /lowCD33+ CD16– ) expanded by granulocyte colony-stimulating factor prevent acute graft-versus-host disease (GVHD) in humanized mouse and might contribute to lower GVHD in patients post allo-HSCT. J Hematol Oncol. 2019; 12(1): 31. DOI: 10.1186/s13045-019-0710-0.Wang K., Lv M., Chang Y.J., et al. Early myeloid-derived suppressor cells (HLA-DR– /lowCD33+ CD16– ) expanded by granulocyte colony-stimulating factor prevent acute graft-versus-host disease (GVHD) in humanized mouse and might contribute to lower GVHD in patients post allo-HSCT. J Hematol Oncol. 2019; 12(1): 31. DOI: 10.1186/s13045-019-0710-0.Vendramin A., Gimondi S., Bermema A., et al. Graft monocytic myeloid-derived suppressor cell content predicts the risk of acute graft-versus-host disease after allogeneic transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood stem cells. Biol Blood Marrow Transplant. 2014; 20(12): 2049–2055. DOI: 10.1016/j.bbmt.2014.09.011.Vendramin A., Gimondi S., Bermema A., et al. Graft monocytic myeloid-derived suppressor cell content predicts the risk of acute graft-versus-host disease after allogeneic transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood stem cells. Biol Blood Marrow Transplant. 2014; 20(12): 2049–2055. DOI: 10.1016/j.bbmt.2014.09.011.Rajkumar S.V. Multiple myeloma: 2018 update on diagnosis, risk‐stratifi cation and management. Am J Hematol. 2018; 93(8): 981–1114. DOI: 10.1002/ajh.25117.Rajkumar S.V. Multiple myeloma: 2018 update on diagnosis, risk‐stratifi cation and management. Am J Hematol. 2018; 93(8): 981–1114. DOI: 10.1002/ajh.25117.Kumar S.K., Rajkumar S.V., Dispenzieri A., et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008; 111(5): 2516–2020. DOI: 10.1182/blood-2007-10-116129.Kumar S.K., Rajkumar S.V., Dispenzieri A., et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008; 111(5): 2516–2020. DOI: 10.1182/blood-2007-10-116129.Robak P., Drozdz I., Szemraj J., Robak T. Drug resistance in multiple myeloma. Cancer Treat Rev. 2018; 70: 199–208. DOI: 10.1016/j.ctrv.2018.09.001.Robak P., Drozdz I., Szemraj J., Robak T. Drug resistance in multiple myeloma. Cancer Treat Rev. 2018; 70: 199–208. DOI: 10.1016/j.ctrv.2018.09.001.Malek E., de Lima M., Letterio J.J., et al. Myeloid-derived suppressor cells: The green light for myeloma immune escape. Blood Rev. 2016; 30(5): 341–348. DOI: 10.1016/j.blre.2016.04.002.Malek E., de Lima M., Letterio J.J., et al. Myeloid-derived suppressor cells: The green light for myeloma immune escape. Blood Rev. 2016; 30(5): 341–348. DOI: 10.1016/j.blre.2016.04.002.Romano A., Conticello C., Cavalli M., et al. Immunological dysregulation in multiple myeloma microenvironment. Biomed Res Int. 2014; 2014: 198539. DOI: 10.1155/2014/198539.Romano A., Conticello C., Cavalli M., et al. Immunological dysregulation in multiple myeloma microenvironment. Biomed Res Int. 2014; 2014: 198539. DOI: 10.1155/2014/198539.De Veirman K., Menu E., Maes K., et al. Myeloid-derived suppressor cells induce multiple myeloma cell survival by activating the AMPK pathway. Cancer Lett. 2019; 442: 233–241. DOI: 10.1016/j.canlet.2018.11.002.De Veirman K., Menu E., Maes K., et al. Myeloid-derived suppressor cells induce multiple myeloma cell survival by activating the AMPK pathway. Cancer Lett. 2019; 442: 233–241. DOI: 10.1016/j.canlet.2018.11.002.Ramachandran I.R., Condamine T., Lin C., et al. Bone marrow PMN-MDSCs and neutrophils are functionally similar in protection of multiple myeloma from chemotherapy. Cancer Lett. 2016; 371(1): 117–124. DOI: 10.1016/j.canlet.2015.10.040.Ramachandran I.R., Condamine T., Lin C., et al. Bone marrow PMN-MDSCs and neutrophils are functionally similar in protection of multiple myeloma from chemotherapy. Cancer Lett. 2016; 371(1): 117–124. DOI: 10.1016/j.canlet.2015.10.040.Lee S.E., Lim J.Y., Kim T.W., et al. Different role of circulating myeloid-derived suppressor cells in patients with multiple myeloma undergoing autologous stem cell transplantation. J Immunother Cancer. 2019; 7(1): 35. DOI: 10.1186/s40425-018-0491-y.Lee S.E., Lim J.Y., Kim T.W., et al. Different role of circulating myeloid-derived suppressor cells in patients with multiple myeloma undergoing autologous stem cell transplantation. J Immunother Cancer. 2019; 7(1): 35. DOI: 10.1186/s40425-018-0491-y.Palumbo G.A., Parrinello N.L., Giallongo C., et al. Monocytic myeloid derived suppressor cells in hematological malignancies. Int J Mol Sci. 2019; 20(21): 54–59. DOI: 10.3390/ijms20215459.Palumbo G.A., Parrinello N.L., Giallongo C., et al. Monocytic myeloid derived suppressor cells in hematological malignancies. Int J Mol Sci. 2019; 20(21): 54–59. DOI: 10.3390/ijms20215459.De Veirman K., Van Valckenborgh E., Lahmar Q., et al. Myeloid-derived suppressor cells as therapeutic target in hematological malignancies. Front Oncol. 2014; 4: 349. DOI: 10.3389/fonc.2014.00349.De Veirman K., Van Valckenborgh E., Lahmar Q., et al. Myeloid-derived suppressor cells as therapeutic target in hematological malignancies. Front Oncol. 2014; 4: 349. DOI: 10.3389/fonc.2014.00349.Менделеева Л.П., Вотякова О.М., Покровская О.С. и др. Национальные клинические рекомендации по диагностике и лечению множественной миеломы. Гематология и трансфузиология. 2016; 61(1, Прил. 2): 1–24. DOI: 10.18821/0234-5730-2016-61-1.Mendeleeva L.P., Votyakova O.M., Pokrovskaya O.S., et al. National clinical guidelines for the diagnosis and treatment of multiple myeloma. Gematologiya i Transfusiologiya. 2016; 61(Supp. 2): 1–24. DOI: 10.18821/0234-5730-2016-61-1. (In Russian).Li L., Wang L. Multiple myeloma: What do we do about immunodefi ciency. J Cancer. 2019; 10(7): 1675–1684. DOI: 10.7150/jca.29993.Li L., Wang L. Multiple myeloma: What do we do about immunodefi ciency. J Cancer. 2019; 10(7): 1675–1684. DOI: 10.7150/jca.29993.Brimnes M.K., Vangsted A.J., Knudsen L.M., et al. Increased level of both CD4+ FOXP3+ regulatory T cells and CD14+ HLA-DR– /low myeloid-derived suppressor cells and decreased level of dendritic cells in patients with multiple myeloma. Scand J Immunol. 2010; 72(6): 540–547. DOI: 10.1111/j.1365-3083.2010.02463.Brimnes M.K., Vangsted A.J., Knudsen L.M., et al. Increased level of both CD4+ FOXP3+ regulatory T cells and CD14+ HLA-DR– /low myeloid-derived suppressor cells and decreased level of dendritic cells in patients with multiple myeloma. Scand J Immunol. 2010; 72(6): 540–547. DOI: 10.1111/j.1365-3083.2010.02463.Wang Z., Zhang L., Wang H., et al. Tumor-induced CD14+ HLA-DR−/low myeloid-derived suppressor cells correlate with tumor progression and outcome of therapy in multiple myeloma patients. Cancer Immunol Immunother. 2015; 64: 389–399. DOI: 10.1007/s00262-014-1646-4.Wang Z., Zhang L., Wang H., et al. Tumor-induced CD14+ HLA-DR−/low myeloid-derived suppressor cells correlate with tumor progression and outcome of therapy in multiple myeloma patients. Cancer Immunol Immunother. 2015; 64: 389–399. DOI: 10.1007/s00262-014-1646-4.Favaloro J., Liyadipitiya T., Brown R., et al. Myeloid derived suppressor cells are numerically, functionally and phenotypically different in patients with multiple myeloma. Leuk Lymphoma. 2014; 55(12): 2893–2900. DOI: 10.3109/10428194.2014.904511.Favaloro J., Liyadipitiya T., Brown R., et al. Myeloid derived suppressor cells are numerically, functionally and phenotypically different in patients with multiple myeloma. Leuk Lymphoma. 2014; 55(12): 2893–2900. DOI: 10.3109/10428194.2014.904511.Görgün G.T., Whitehill G., Anderson J.L., et al. Tumor-promoting immunesuppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood. 2013; 121(15): 2975–2987. DOI: 10.1182/blood-2012-08-448548.Görgün G.T., Whitehill G., Anderson J.L., et al. Tumor-promoting immunesuppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood. 2013; 121(15): 2975–2987. DOI: 10.1182/blood-2012-08-448548.Ramachandran I.R., Martner A., Pisklakova A., et al. Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow. J Immunol. 2013; 190(7): 3815–3823. DOI: 10.4049/jimmunol.1203373.Ramachandran I.R., Martner A., Pisklakova A., et al. Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow. J Immunol. 2013; 190(7): 3815–3823. DOI: 10.4049/jimmunol.1203373.Binsfeld M., Muller J., Lamour V., et al. Granulocytic myeloid-derived suppressor cells promote angiogenesis in the context of multiple myeloma. Oncotarget. 2016; 7(25): 37931–37943. DOI: 10.18632/oncotarget.9270.Binsfeld M., Muller J., Lamour V., et al. Granulocytic myeloid-derived suppressor cells promote angiogenesis in the context of multiple myeloma. Oncotarget. 2016; 7(25): 37931–37943. DOI: 10.18632/oncotarget.9270.Ai L., Mu S., Sun C., et al. Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation. Mol Cancer. 2019; 18(10): 88. DOI: 10.1186/s12943-019-1011-5.Ai L., Mu S., Sun C., et al. Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation. Mol Cancer. 2019; 18(10): 88. DOI: 10.1186/s12943-019-1011-5.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. 2012; 26(11): 2424. DOI: 10.1038/leu.2012.113.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. 2012; 26(11): 2424. DOI: 10.1038/leu.2012.113.Batorov E.V., Tikhonova M.A., Pronkina N.V., et al. Increased circulating CD4+ FOXP3+ T cells associate with early relapse following autologous hematopoietic stem cell transplantation in multiple myeloma patients. Oncotarget. 2018; 9: 27305–27317. DOI: 10.18632/oncotarget.25553.Batorov E.V., Tikhonova M.A., Pronkina N.V., et al. Increased circulating CD4+ FOXP3+ T cells associate with early relapse following autologous hematopoietic stem cell transplantation in multiple myeloma patients. Oncotarget. 2018; 9: 27305–27317. DOI: 10.18632/oncotarget.25553.

The authors declare that there are no conflicts of interest present.