{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T12:45:31Z","timestamp":1777293931125,"version":"3.51.4"},"reference-count":123,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T00:00:00Z","timestamp":1612483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/MEC-HEM\/30315\/2017"],"award-info":[{"award-number":["PTDC\/MEC-HEM\/30315\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014069","name":"Funda\u00e7\u00e3o Champalimaud","doi-asserted-by":"publisher","award":["Internal Funding"],"award-info":[{"award-number":["Internal Funding"]}],"id":[{"id":"10.13039\/501100014069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Multiple myeloma (MM) is one of the most prevalent hematological cancers worldwide, characterized by the clonal expansion of neoplastic plasma cells in the bone marrow (BM). A combination of factors is implicated in disease progression, including BM immune microenvironment changes. Increasing evidence suggests that the disruption of immunological processes responsible for myeloma control ultimately leads to the escape from immune surveillance and resistance to immune effector function, resulting in an active form of myeloma. In fact, one of the hallmarks of MM is the development of a permissive BM milieu that provides a growth advantage to the malignant cells. Consequently, a better understanding of how myeloma cells interact with the BM niche compartments and disrupt the immune homeostasis is of utmost importance to develop more effective treatments. This review focuses on the most up-to-date knowledge regarding microenvironment-related mechanisms behind MM immune evasion and suppression, as well as promising molecules that are currently under pre-clinical tests targeting immune populations.<\/jats:p>","DOI":"10.3390\/cancers13040625","type":"journal-article","created":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T00:54:35Z","timestamp":1612486475000},"page":"625","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["The Immune Microenvironment in Multiple Myeloma: Friend or Foe?"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2378-6192","authenticated-orcid":false,"given":"Raquel","family":"Lopes","sequence":"first","affiliation":[{"name":"Lymphoma and Myeloma Research Programme, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal"},{"name":"Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8956-6726","authenticated-orcid":false,"given":"Joana","family":"Caetano","sequence":"additional","affiliation":[{"name":"Lymphoma and Myeloma Research Programme, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal"},{"name":"Hemato-Oncology Department, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal"},{"name":"Faculty of Medical Sciences, NOVA Medical School, 1169-056 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5612-5385","authenticated-orcid":false,"given":"Bruna","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Lymphoma and Myeloma Research Programme, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal"},{"name":"Faculty of Medical Sciences, NOVA Medical School, 1169-056 Lisbon, Portugal"}]},{"given":"Filipa","family":"Barahona","sequence":"additional","affiliation":[{"name":"Lymphoma and Myeloma Research Programme, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal"},{"name":"Faculty of Medical Sciences, NOVA Medical School, 1169-056 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5235-6557","authenticated-orcid":false,"given":"Emilie Arnault","family":"Carneiro","sequence":"additional","affiliation":[{"name":"Lymphoma and Myeloma Research Programme, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal"}]},{"given":"Cristina","family":"Jo\u00e3o","sequence":"additional","affiliation":[{"name":"Lymphoma and Myeloma Research Programme, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal"},{"name":"Hemato-Oncology Department, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal"},{"name":"Faculty of Medical Sciences, NOVA Medical School, 1169-056 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R.L., Torre, L.A., and Jemal, A. (2018). Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA. Cancer J. Clin., 394\u2013424.","DOI":"10.3322\/caac.21492"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1056\/NEJMra1011442","article-title":"Multiple myeloma","volume":"364","author":"Palumbo","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e538","DOI":"10.1016\/S1470-2045(14)70442-5","article-title":"International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma","volume":"15","author":"Rajkumar","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5412","DOI":"10.1182\/blood-2008-12-194241","article-title":"Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: A prospective study","volume":"113","author":"Landgren","year":"2014","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-319-40320-5_1","article-title":"MGUS and Smoldering Multiple Myeloma: Diagnosis and Epidemiology","volume":"169","author":"Mateos","year":"2016","journal-title":"Cancer Treat. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"157496","DOI":"10.1155\/2012\/157496","article-title":"Bone marrow microenvironment in multiple myeloma progression","volume":"2012","author":"Manier","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/imr.12233","article-title":"Targeting the bone marrow microenvironment in multiple myeloma","volume":"263","author":"Moschetta","year":"2015","journal-title":"Immunol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1038\/leu.2017.138","article-title":"Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: A multicenter IMWG study","volume":"31","author":"Kumar","year":"2017","journal-title":"Leukemia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"699","DOI":"10.3389\/fonc.2019.00699","article-title":"Minimal Residual Disease Assessment Within the Bone Marrow of Multiple Myeloma: A Review of Caveats, Clinical Significance and Future Perspectives","volume":"9","author":"Romano","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1158\/0008-5472.CAN-14-3400","article-title":"Metabolic signature identifies novel targets for drug resistance in multiple myeloma","volume":"75","author":"Maiso","year":"2015","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tibullo, D., Longo, A., Vicario, N., Romano, A., Barbato, A., Di Rosa, M., Barbagallo, I., Anfuso, C.D., Lupo, G., and Gulino, R. (2020). Ixazomib Improves Bone Remodeling and Counteracts sonic Hedgehog signaling Inhibition Mediated by Myeloma Cells. Cancers, 12.","DOI":"10.3390\/cancers12020323"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"163","DOI":"10.3324\/haematol.2013.090977","article-title":"Myeloma plasma cells alter the bone marrow microenvironment by stimulating the proliferation of mesenchymal stromal cells","volume":"99","author":"Noll","year":"2014","journal-title":"Haematologica"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1146\/annurev.immunol.22.012703.104803","article-title":"The Three Es of Cancer Immunoediting","volume":"22","author":"Dunn","year":"2004","journal-title":"Annu. Rev. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s43018-020-0053-3","article-title":"Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma","volume":"1","author":"Zavidij","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1038\/leu.2013.86","article-title":"Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma","volume":"27","author":"Rajkumar","year":"2013","journal-title":"Leukemia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1182\/asheducation-2013.1.478","article-title":"Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: Biological insights and early treatment strategies","volume":"2013","author":"Landgren","year":"2013","journal-title":"Hematol. Am. Soc. Hematol. Educ. Progr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1182\/blood-2006-03-009910","article-title":"Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: Incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantati","volume":"108","author":"Hanamura","year":"2006","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nrclinonc.2016.122","article-title":"Genomic complexity of multiple myeloma and its clinical implications","volume":"14","author":"Manier","year":"2016","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bailur, J.K., McCachren, S.S., Doxie, D.B., Shrestha, M., Pendleton, K., Nooka, A.K., Neparidze, N., Parker, T.L., Bar, N., and Kaufman, J.L. (2019). Early alterations in stem-like\/resident T cells, innate and myeloid cells in the bone marrow in preneoplastic gammopathy. JCI Insight, 5.","DOI":"10.1172\/jci.insight.127807"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"79","DOI":"10.3324\/haematol.2012.067272","article-title":"Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry","volume":"98","author":"Vidriales","year":"2013","journal-title":"Haematologica"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1182\/blood-2018-01-825240","article-title":"Myeloma escape after stem cell transplantation is a consequence of T-cell exhaustion and is prevented by TIGIT blockade","volume":"132","author":"Minnie","year":"2018","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3625","DOI":"10.1182\/blood-2009-05-220285","article-title":"Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug\u2014Induced apoptosis","volume":"114","author":"Zheng","year":"2009","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/nri2506","article-title":"Myeloid-derived suppressor cells as regulators of the immune system","volume":"9","author":"Gabrilovich","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1084\/jem.20062602","article-title":"MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis","volume":"204","author":"Delano","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.it.2016.01.004","article-title":"The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment","volume":"37","author":"Kumar","year":"2016","journal-title":"Trends Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4233","DOI":"10.1182\/blood-2007-07-099226","article-title":"Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell\u2013suppressive activity","volume":"111","author":"Movahedi","year":"2008","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"37931","DOI":"10.18632\/oncotarget.9270","article-title":"Granulocytic myeloid-derived suppressor cells promote angiogenesis in the context of multiple myeloma","volume":"7","author":"Binsfeld","year":"2016","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3815","DOI":"10.4049\/jimmunol.1203373","article-title":"Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow","volume":"190","author":"Ramachandran","year":"2013","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1111\/j.1365-3083.2010.02463.x","article-title":"Increased level of both CD4+FOXP3+ regulatory T cells and CD14+HLA-DR\u2212\/low myeloid-derived suppressor cells and decreased level of dendritic cells in patients with multiple myeloma","volume":"72","author":"Brimnes","year":"2010","journal-title":"Scand. J. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.1182\/blood-2012-08-448548","article-title":"Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans","volume":"121","author":"Whitehill","year":"2013","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1038\/leu.2012.113","article-title":"Multiple myeloma induces the immunosuppressive capacity of distinct myeloid-derived suppressor cell subpopulations in the bone marrow","volume":"26","author":"Schouppe","year":"2012","journal-title":"Leukemia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.3109\/10428194.2014.904511","article-title":"Myeloid derived suppressor cells are numerically, functionally and phenotypically different in patients with multiple myeloma","volume":"55","author":"Favaloro","year":"2014","journal-title":"Leuk. Lymphoma"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s00262-014-1646-4","article-title":"Tumor-induced CD14+HLA-DR (-\/low) myeloid-derived suppressor cells correlate with tumor progression and outcome of therapy in multiple myeloma patients","volume":"64","author":"Wang","year":"2015","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1111\/j.1365-2567.2012.03566.x","article-title":"S100A9 a new marker for monocytic human myeloid-derived suppressor cells","volume":"136","author":"Zhao","year":"2012","journal-title":"Immunology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.canlet.2015.10.040","article-title":"Bone marrow PMN-MDSCs and neutrophils are functionally similar in protection of multiple myeloma from chemotherapy","volume":"371","author":"Ramachandran","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"43992","DOI":"10.18632\/oncotarget.6083","article-title":"The bone marrow microenvironment enhances multiple myeloma progression by exosome-mediated activation of myeloid-derived suppressor cells","volume":"6","author":"Wang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.3389\/fonc.2020.01362","article-title":"Dual Targeting to Overcome Current Challenges in Multiple Myeloma CAR T-Cell Treatment","volume":"10","author":"Mutis","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1007\/s00262-011-1143-y","article-title":"Myeloid-derived suppressor cells impair the quality of dendritic cell vaccines","volume":"61","author":"Poschke","year":"2012","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_39","first-page":"99","article-title":"Macrophage functions in wound healing","volume":"13","author":"Kloc","year":"2019","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.immuni.2014.06.010","article-title":"Tumor-associated macrophages: From mechanisms to therapy","volume":"41","author":"Noy","year":"2014","journal-title":"Immunity"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.canlet.2013.01.024","article-title":"Tumor-associated macrophages as potential diagnostic and prognostic biomarkers in breast cancer","volume":"332","author":"Tang","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Lopez-Yrigoyen, M., Cassetta, L., and Pollard, J.W. (2020). Macrophage targeting in cancer. Ann. N. Y. Acad. Sci.","DOI":"10.1111\/nyas.14377"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1007\/s00277-012-1652-6","article-title":"Tumor-associated macrophages as a prognostic parameter in multiple myeloma","volume":"92","author":"Sucak","year":"2013","journal-title":"Ann. Hematol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1038\/leu.2015.191","article-title":"Tumor-associated macrophages and extracellular matrix metalloproteinase inducer in prognosis of multiple myeloma","volume":"30","author":"Panchabhai","year":"2016","journal-title":"Leukemia"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3239","DOI":"10.7150\/jca.30102","article-title":"High numbers of CD163 + tumor-associated macrophages correlate with poor prognosis in multiple myeloma patients receiving bortezomib-based regimens","volume":"10","author":"Wang","year":"2019","journal-title":"J. Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1158\/1541-7786.MCR-19-0487","article-title":"Pro-inflammatory macrophages promote multiple myeloma resistance to bortezomib therapy","volume":"17","author":"Magidey","year":"2019","journal-title":"Mol. Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11283","DOI":"10.18632\/oncotarget.2207","article-title":"Multiple myeloma cells recruit tumor-supportive macrophages through the CXCR4\/CXCL12 axis and promote their polarization toward the M2 phenotype","volume":"5","author":"Beider","year":"2014","journal-title":"Oncotarget"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1182\/blood-2016-01-695395","article-title":"Evaluation of the potential therapeutic benefits of macrophage reprogramming in multiple myeloma","volume":"128","author":"Samaniego","year":"2016","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/32588","article-title":"Dendritic cells and the control of immunity","volume":"392","author":"Banchereau","year":"1998","journal-title":"Nature"},{"key":"ref_50","first-page":"487","article-title":"Human blood contains two subsets of dendritic cells, one immunologically mature and the other immature","volume":"82","author":"Peng","year":"1994","journal-title":"Immunology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.vetimm.2009.10.012","article-title":"Utilizing the FIV model to understand dendritic cell dysfunction and the potential role of dendritic cell immunization in HIV infection","volume":"134","author":"Lehman","year":"2010","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1084\/jem.20051395","article-title":"Production of type I interferons: Plasmacytoid dendritic cells and beyond","volume":"202","author":"Trinchieri","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2992","DOI":"10.1182\/blood.V98.10.2992","article-title":"Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-beta1 and interleukin-10","volume":"98","author":"Brown","year":"2001","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4071","DOI":"10.1182\/blood-2006-04-016980","article-title":"Optimizing immunotherapy in multiple myeloma: Restoring the function of patients\u2019 monocyte-derived dendritic cells by inhibiting p38 or activating MEK\/ERK MAPK and neutralizing interleukin-6 in progenitor cells","volume":"108","author":"Wang","year":"2006","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1084\/jem.20052136","article-title":"Enhancement of clonogenicity of human multiple myeloma by dendritic cells","volume":"203","author":"Kukreja","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5705","DOI":"10.1038\/s41598-018-23943-w","article-title":"Compromised functionality of monocyte-derived dendritic cells in multiple myeloma patients may limit their use in cancer immunotherapy","volume":"8","author":"Shinde","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1111\/bjh.12333","article-title":"Immature dendritic cells in multiple myeloma are prone to osteoclast-like differentiation through interleukin-17A stimulation","volume":"161","author":"Tucci","year":"2013","journal-title":"Br. J. Haematol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/j.1365-2249.2006.03037.x","article-title":"Impaired functionality and phenotypic profile of dendritic cells from patients with multiple myeloma","volume":"144","author":"Brimnes","year":"2006","journal-title":"Clin. Exp. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.ccr.2009.08.019","article-title":"Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: A therapeutic target","volume":"16","author":"Chauhan","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1182\/blood.V100.1.230","article-title":"Dendritic cells are functionally defective in multiple myeloma: The role of interleukin-6","volume":"100","author":"Ratta","year":"2002","journal-title":"Blood"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1111\/j.1365-2141.2000.02413.x","article-title":"Expression and production of interleukin 10 in human myeloma cell lines","volume":"111","author":"Otsuki","year":"2000","journal-title":"Br. J. Haematol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1046\/j.1365-2141.2000.02020.x","article-title":"Activity of interleukin 6 in the differentiation of monocytes to macrophages and dendritic cells","volume":"109","author":"Mitani","year":"2000","journal-title":"Br. J. Haematol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1182\/blood-2009-06-228676","article-title":"Alterations in the antigen processing-presenting machinery of transformed plasma cells are associated with reduced recognition by CD8+ T cells and characterize the progression of MGUS to multiple myeloma","volume":"115","author":"Racanelli","year":"2010","journal-title":"Blood"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1182\/blood-2015-01-623975","article-title":"Dendritic cells accumulate in the bone marrow of myeloma patients where they protect tumor plasma cells from CD8+ T-cell killing","volume":"126","author":"Leone","year":"2015","journal-title":"Blood"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1182\/blood-2019-123333","article-title":"Interaction of Plasmacytoid Dendritic Cells and Myeloma Cells Trigger Tumor Promoting Transcriptional Changes in Multiple Myeloma Cells","volume":"134","author":"Ray","year":"2019","journal-title":"Blood"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1158\/1078-0432.CCR-19-2111","article-title":"V How to Train Your T Cells: Overcoming Immune Dysfunction in Multiple Myeloma","volume":"26","author":"Cohen","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1111\/j.1365-2141.2008.07530.x","article-title":"CD4(+)CD25(+)FoxP3(+) regulatory T cells are increased whilst CD3(+)CD4(-)CD8(-)alphabetaTCR(+) Double Negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden","volume":"144","author":"Feyler","year":"2009","journal-title":"Br. J. Haematol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1182\/blood-2015-10-662320","article-title":"Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: A longitudinal analysis","volume":"127","author":"Paiva","year":"2016","journal-title":"Blood"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1084\/jem.20031030","article-title":"Vigorous premalignancy-specific effector T cell response in the bone marrow of patients with monoclonal gammopathy","volume":"198","author":"Dhodapkar","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00109-015-1345-4","article-title":"Dissecting the multiple myeloma-bone microenvironment reveals new therapeutic opportunities","volume":"94","author":"Shay","year":"2016","journal-title":"J. Mol. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1097\/CJI.0b013e31821ca6ce","article-title":"PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell\/myeloma fusion vaccine","volume":"34","author":"Rosenblatt","year":"2011","journal-title":"J. Immunother."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1038\/leu.2015.11","article-title":"Targeting PD1-PDL1 immune checkpoint in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cells","volume":"29","author":"Ray","year":"2015","journal-title":"Leukemia"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1158\/2326-6066.CIR-15-0055","article-title":"T-cell Exhaustion in Multiple Myeloma Relapse after Autotransplant: Optimal Timing of Immunotherapy","volume":"4","author":"Chung","year":"2016","journal-title":"Cancer Immunol. Res."},{"key":"ref_74","first-page":"304","article-title":"Bone marrow PD-1 positive T cells reflect tumor mass and prognosis in multiple myeloma","volume":"11","author":"Chang","year":"2018","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1038\/leu.2013.310","article-title":"Coinhibitory molecule PD-1 as a potential target for the immunotherapy of multiple myeloma","volume":"28","author":"Atanackovic","year":"2014","journal-title":"Leukemia"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1182\/blood-2018-01-825265","article-title":"TIGIT immune checkpoint blockade restores CD8(+) T-cell immunity against multiple myeloma","volume":"132","author":"Guillerey","year":"2018","journal-title":"Blood"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1182\/blood-2015-03-632919","article-title":"Prospective analysis of antigen-specific immunity, stem-cell antigens, and immune checkpoints in monoclonal gammopathy","volume":"126","author":"Dhodapkar","year":"2015","journal-title":"Blood"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3227","DOI":"10.1182\/blood-2010-04-279893","article-title":"Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma","volume":"116","author":"Calabrese","year":"2010","journal-title":"Blood"},{"key":"ref_79","first-page":"1","article-title":"Immunological dysregulation in multiple myeloma microenvironment","volume":"2014","author":"Romano","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1182\/blood-2005-08-3101","article-title":"Dysfunctional T regulatory cells in multiple myeloma","volume":"107","author":"Prabhala","year":"2006","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Muthu Raja, K.R., Kubiczkova, L., Rihova, L., Piskacek, M., Vsianska, P., Hezova, R., Pour, L., and Hajek, R. (2012). Functionally suppressive CD8 T regulatory cells are increased in patients with multiple myeloma: A cause for immune impairment. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049446"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1186\/s12935-018-0687-8","article-title":"Increased activated regulatory T cell subsets and aging Treg-like cells in multiple myeloma and monoclonal gammopathy of undetermined significance: A case control study","volume":"18","author":"Wang","year":"2018","journal-title":"Cancer Cell Int."},{"key":"ref_83","first-page":"e148","article-title":"Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg\/Th17 balance","volume":"3","author":"Bryant","year":"2013","journal-title":"Blood"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1007\/s00277-019-03657-3","article-title":"Evaluation of regulatory T cells (Tregs) alterations in patients with multiple myeloma treated with bortezomib or lenalidomide plus dexamethasone: Correlations with treatment outcome","volume":"98","author":"Hadjiaggelidou","year":"2019","journal-title":"Ann. Hematol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1182\/blood-2015-12-687749","article-title":"Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma","volume":"128","author":"Krejcik","year":"2016","journal-title":"Blood"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1158\/1078-0432.CCR-06-1603","article-title":"Long-term idiotype vaccination combined with interleukin-12 (IL-12), or IL-12 and granulocyte macrophage colony-stimulating factor, in early-stage multiple myeloma patients","volume":"13","author":"Hansson","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/nri2781","article-title":"Gammadelta T cell effector functions: A blend of innate programming and acquired plasticity","volume":"10","author":"Bonneville","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1182\/blood.V96.2.384.013k07_384_392","article-title":"Stimulation of gammadelta T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma","volume":"96","author":"Kunzmann","year":"2000","journal-title":"Blood"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1182\/blood-2002-12-3665","article-title":"Gammadelta T cells for immune therapy of patients with lymphoid malignancies","volume":"102","author":"Wilhelm","year":"2003","journal-title":"Blood"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"7502","DOI":"10.1158\/0008-5472.CAN-05-0731","article-title":"MICA expressed by multiple myeloma and monoclonal gammopathy of undetermined significance plasma cells Costimulates pamidronate-activated gammadelta lymphocytes","volume":"65","author":"Girlanda","year":"2005","journal-title":"Cancer Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1182\/blood-2004-04-1422","article-title":"HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells","volume":"105","author":"Carbone","year":"2005","journal-title":"Blood"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"8444","DOI":"10.1158\/0008-5472.CAN-06-4230","article-title":"The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells","volume":"67","author":"Meade","year":"2007","journal-title":"Cancer Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.4161\/cbt.8.23.10455","article-title":"Natural killer cells and cancer: Regulation by the killer cell Ig-like receptors (KIR)","volume":"8","author":"Purdy","year":"2009","journal-title":"Cancer Biol. Ther."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/nri2604","article-title":"Oncogenic stress sensed by the immune system: Role of natural killer cell receptors","volume":"9","author":"Raulet","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1046\/j.1365-2141.2002.03879.x","article-title":"Anti-myeloma activity of natural killer lymphocytes","volume":"119","author":"Frohn","year":"2002","journal-title":"Br. J. Haematol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1073\/pnas.0711293105","article-title":"MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma","volume":"105","author":"Jinushi","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Feyler, S., Scott, G.B., Parrish, C., Jarmin, S., Evans, P., Short, M., McKinley, K., Selby, P.J., and Cook, G. (2012). Tumour Cell Generation of Inducible Regulatory T-Cells in Multiple Myeloma Is Contact-Dependent and Antigen-Presenting Cell-Independent. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035981"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1111\/imm.12082","article-title":"Differential expression of natural killer cell activating receptors in blood versus bone marrow in patients with monoclonal gammopathy","volume":"139","author":"Costello","year":"2013","journal-title":"Immunology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.3109\/10428194.2012.676175","article-title":"The role of natural killer cells in immunity against multiple myeloma","volume":"53","author":"Godfrey","year":"2012","journal-title":"Leuk. Lymphoma"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1007\/s12032-007-0007-y","article-title":"Clinical stage-depending decrease of NK cell activity in multiple myeloma patients","volume":"24","author":"Jurisic","year":"2007","journal-title":"Med. Oncol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s002770050397","article-title":"Lymphocyte profiles in multiple myeloma and monoclonal gammopathy of undetermined significance: Flow-cytometric characterization and analysis in a two-dimensional correlation biplot","volume":"76","author":"Meeus","year":"1998","journal-title":"Ann. Hematol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/BF00199953","article-title":"Surface markers and cytotoxic activities of lymphocytes in monoclonal gammopathy of undetermined significance and untreated multiple myeloma. Increased phytohemagglutinin-induced cellular cytotoxicity and inverted helper\/suppressor cell ratio are features","volume":"25","author":"Bottari","year":"1987","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1111\/j.1365-2257.1994.tb00414.x","article-title":"Peripheral blood lymphocyte subsets in multiple myeloma and monoclonal gammopathy of undetermined significance","volume":"16","author":"Tienhaara","year":"1994","journal-title":"Clin. Lab. Haematol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e547","DOI":"10.1038\/bcj.2017.24","article-title":"Regulatory B cell-myeloma cell interaction confers immunosuppression and promotes their survival in the bone marrow milieu","volume":"7","author":"Zhang","year":"2017","journal-title":"Blood Cancer J."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1182\/blood-2019-128703","article-title":"Onset of Regulatory B Cells Occurs at Initial Stage of B Cell Dysfunction in Multiple Myeloma","volume":"134","author":"Zou","year":"2019","journal-title":"Blood"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1038\/cmi.2017.35","article-title":"B cell regulation in cancer and anti-tumor immunity","volume":"14","author":"Sarvaria","year":"2017","journal-title":"Cell. Mol. Immunol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1002\/ijc.21177","article-title":"Increased rejection of primary tumors in mice lacking B cells: Inhibition of anti-tumor CTL and TH1 cytokine responses by B cells","volume":"117","author":"Shah","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nm0598-627","article-title":"B cells inhibit induction of T cell-dependent tumor immunity","volume":"4","author":"Qin","year":"1998","journal-title":"Nat. Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"7741","DOI":"10.1158\/0008-5472.CAN-05-3766","article-title":"Inhibitory effects of B cells on antitumor immunity","volume":"66","author":"Inoue","year":"2006","journal-title":"Cancer Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"5569","DOI":"10.4049\/jimmunol.1100284","article-title":"Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1\/Th17 but a decrease in regulatory T cells","volume":"186","author":"Carter","year":"2011","journal-title":"J. Immunol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"3505","DOI":"10.1158\/0008-5472.CAN-10-4316","article-title":"Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+ T cells to T-regulatory cells","volume":"71","author":"Olkhanud","year":"2011","journal-title":"Cancer Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s40425-016-0145-x","article-title":"B cell regulation of the anti-tumor response and role in carcinogenesis","volume":"4","author":"Schwartz","year":"2016","journal-title":"J. Immunother. Cancer"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41375-018-0242-6","article-title":"APRIL signaling via TACI mediates immunosuppression by T regulatory cells in multiple myeloma: Therapeutic implications","volume":"33","author":"Tai","year":"2019","journal-title":"Leukemia"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Bosseboeuf, A., Feron, D., Tallet, A., Rossi, C., Charlier, C., Garderet, L., Caillot, D., Moreau, P., Card\u00f3-Vila, M., and Pasqualini, R. (2017). Monoclonal IgG in MGUS and multiple myeloma targets infectious pathogens. JCI Insight, 2.","DOI":"10.1172\/jci.insight.95367"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Nair, S., Sng, J., Boddupalli, C.S., Seckinger, A., Chesi, M., Fulciniti, M., Zhang, L., Rauniyar, N., Lopez, M., and Neparidze, N. (2018). Antigen-mediated regulation in monoclonal gammopathies and myeloma. JCI Insight, 3.","DOI":"10.1172\/jci.insight.98259"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1056\/NEJMoa1508808","article-title":"V Clonal Immunoglobulin against Lysolipids in the Origin of Myeloma","volume":"374","author":"Nair","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Nakamura, K., Kassem, S., Cleynen, A., Chr\u00e9tien, M.-L., Guillerey, C., Putz, E.M., Bald, T., F\u00f6rster, I., Vuckovic, S., and Hill, G.R. (2018). Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment. Cancer Cell, 634\u2013648.","DOI":"10.1016\/j.ccell.2018.02.007"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/s12943-019-1011-5","article-title":"Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation","volume":"18","author":"Ai","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.3389\/fimmu.2018.01370","article-title":"Lenalidomide and programmed death-1 blockade synergistically enhances the effects of dendritic cell vaccination in a model of murine myeloma","volume":"9","author":"Vo","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1038\/leu.2014.46","article-title":"A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib","volume":"28","author":"Ray","year":"2014","journal-title":"Leukemia"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.neo.2019.05.006","article-title":"Clodronate-Liposome Mediated Macrophage Depletion Abrogates Multiple Myeloma Tumor Establishment In Vivo","volume":"21","author":"Opperman","year":"2019","journal-title":"Neoplasia"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1158\/2326-6066.CIR-15-0025-T","article-title":"Tumoricidal Effects of Macrophage-Activating Immunotherapy in a Murine Model of Relapsed\/Refractory Multiple Myeloma","volume":"3","author":"Jensen","year":"2015","journal-title":"Cancer Immunol. Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1158\/2326-6066.CIR-17-0649","article-title":"A CS1-NKG2D Bispecific Antibody Collectively Activates Cytolytic Immune Cells against Multiple Myeloma","volume":"6","author":"Chan","year":"2018","journal-title":"Cancer Immunol. Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/4\/625\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:20:26Z","timestamp":1760160026000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/4\/625"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,5]]},"references-count":123,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["cancers13040625"],"URL":"https:\/\/doi.org\/10.3390\/cancers13040625","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,5]]}}}