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Article

Monocyte Subsets and Serum Inflammatory and Bone-Associated Markers in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

1
Translational and Clinical Research Program, Cancer Research Center (IBMCC, USAL-CSIC), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
2
Biomedical Research Networking Centre Consortium of Oncology (CIBERONC) (CB16/12/00400), Instituto Carlos III, 28029 Madrid, Spain
3
Leiden University Medical Center, Department of Immunology, 2333 ZA Leiden, The Netherlands
4
Institute of Biomedicine of Seville, Department of Hematology, University Hospital Virgen del Rocío of the Consejo Superior de Investigaciones Científicas (CSIC), University of Seville, 41013 Seville, Spain
5
Service of Hematology, University Hospital of Salamanca (CAUSA) and IBSAL, 37007 Salamanca, Spain
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Regulation of the Immune System Group, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Plaza de Cruces 12, 48903 Barakaldo, Spain
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Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), Clinica Universidad de Navarra, 31008 Pamplona, Spain
8
Hematology Service, Hospital Nuestra Señora del Prado, Talavera de la Reina, 45600 Toledo, Spain
9
Primary Health Care Center “Miguel Armijo”, Primary Health Care of Salamanca, Conserjería de Sanidad de Castilla y León (SACYL), 37007 Salamanca, Spain
10
Department of Immunology, Erasmus University Medical Center, 3015 GA Rotterdam, The Netherlands
11
Centro del Cáncer Cedars-Sinai Samuel Oschin, Los Angeles, CA 90048, USA
*
Author to whom correspondence should be addressed.
These authors have equally contributed to this work and should both be considered as last author.
Academic Editor: Sylvie Hermouet
Cancers 2021, 13(6), 1454; https://doi.org/10.3390/cancers13061454
Received: 16 February 2021 / Revised: 16 March 2021 / Accepted: 18 March 2021 / Published: 22 March 2021
(This article belongs to the Special Issue Leukemia and Lymphoma Immunophenotyping)
We investigated the distribution of different subsets of monocytes (Mo) in blood and bone marrow (BM) of newly-diagnosed untreated monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM) and active multiple myeloma (MM), and its relationship with immune/bone serum-marker profiles. Our results showed decreased production of BM Mo with decreased counts of classical Mo (cMo) in BM and blood of SMM and MM, but not MGUS. Conversely, intermediate and non-classical Mo were significantly increased in MGUS, SMM and MM BM. In parallel, increased levels of interleukin (IL)1β were observed in a fraction of MGUS and SMM, while increased serum IL8 was characteristic of SMM and MM, and higher serum IL6, RANKL and bone alkaline phosphatase concentrations, together with decreased counts of FcεRI+cMo, were restricted to MM presenting with bone lesions. These results provide new insights in the pathogenesis of plasma cell neoplasms and the potential role of FcεRI+cMo in normal bone homeostasis.
Background. Monocyte/macrophages have been shown to be altered in monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM) and active multiple myeloma (MM), with an impact on the disruption of the homeostasis of the normal bone marrow (BM) microenvironment. Methods: We investigated the distribution of different subsets of monocytes (Mo) in blood and BM of newly-diagnosed untreated MGUS (n = 23), SMM (n = 14) and MM (n = 99) patients vs. healthy donors (HD; n = 107), in parallel to a large panel of cytokines and bone-associated serum biomarkers. Results: Our results showed normal production of monocyte precursors and classical Mo (cMo) in MGUS, while decreased in SMM and MM (p ≤ 0.02), in association with lower blood counts of recently-produced CD62L+ cMo in SMM (p = 0.004) and of all subsets of (CD62L+, CD62L and FcεRI+) cMo in MM (p ≤ 0.02). In contrast, intermediate and end-stage non-classical Mo were increased in BM of MGUS (p ≤ 0.03), SMM (p ≤ 0.03) and MM (p ≤ 0.002), while normal (MGUS and SMM) or decreased (MM; p = 0.01) in blood. In parallel, increased serum levels of interleukin (IL)1β were observed in MGUS (p = 0.007) and SMM (p = 0.01), higher concentrations of serum IL8 were found in SMM (p = 0.01) and MM (p = 0.002), and higher serum IL6 (p = 0.002), RANKL (p = 0.01) and bone alkaline phosphatase (BALP) levels (p = 0.01) with decreased counts of FcεRI+ cMo, were restricted to MM presenting with osteolytic lesions. This translated into three distinct immune/bone profiles: (1) normal (typical of HD and most MGUS cases); (2) senescent-like (increased IL1β and/or IL8, found in a minority of MGUS, most SMM and few MM cases with no bone lesions); and (3) pro-inflammatory-high serum IL6, RANKL and BALP with significantly (p = 0.01) decreased blood counts of immunomodulatory FcεRI+ cMo-, typical of MM presenting with bone lesions. Conclusions: These results provide new insight into the pathogenesis of plasma cell neoplasms and the potential role of FcεRI+ cMo in normal bone homeostasis. View Full-Text
Keywords: plasma cell neoplasms; MGUS; multiple myeloma; monocytes; FcεRI monocytes; tumor microenvironment; inflammatory cytokines; immunosenescence; bone markers plasma cell neoplasms; MGUS; multiple myeloma; monocytes; FcεRI monocytes; tumor microenvironment; inflammatory cytokines; immunosenescence; bone markers
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MDPI and ACS Style

Damasceno, D.; Almeida, J.; Teodosio, C.; Sanoja-Flores, L.; Mayado, A.; Pérez-Pons, A.; Puig, N.; Arana, P.; Paiva, B.; Solano, F.; Romero, A.; Matarraz, S.; van den Bossche, W.B.L.; Flores-Montero, J.; Durie, B.; van Dongen, J.J.M.; Orfao, A., on behalf of the TiMaScan Study Group. Monocyte Subsets and Serum Inflammatory and Bone-Associated Markers in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma. Cancers 2021, 13, 1454. https://doi.org/10.3390/cancers13061454

AMA Style

Damasceno D, Almeida J, Teodosio C, Sanoja-Flores L, Mayado A, Pérez-Pons A, Puig N, Arana P, Paiva B, Solano F, Romero A, Matarraz S, van den Bossche WBL, Flores-Montero J, Durie B, van Dongen JJM, Orfao A on behalf of the TiMaScan Study Group. Monocyte Subsets and Serum Inflammatory and Bone-Associated Markers in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma. Cancers. 2021; 13(6):1454. https://doi.org/10.3390/cancers13061454

Chicago/Turabian Style

Damasceno, Daniela, Julia Almeida, Cristina Teodosio, Luzalba Sanoja-Flores, Andrea Mayado, Alba Pérez-Pons, Noemi Puig, Paula Arana, Bruno Paiva, Fernando Solano, Alfonso Romero, Sergio Matarraz, Wouter B.L. van den Bossche, Juan Flores-Montero, Brian Durie, Jacques J.M. van Dongen, and Alberto Orfao on behalf of the TiMaScan Study Group. 2021. "Monocyte Subsets and Serum Inflammatory and Bone-Associated Markers in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma" Cancers 13, no. 6: 1454. https://doi.org/10.3390/cancers13061454

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