Gene Expression Analysis of the Bone Marrow Microenvironment Reveals Distinct Immunotypes in Smoldering Multiple Myeloma Associated to Progression to Symptomatic Disease
Isola, Ignacio (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Brasó-Maristany, Fara (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Moreno, David F. (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Mena, Mari Pau (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Oliver-Caldés, Aina (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Paré Brunet, Laia (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Rodríguez Lobato, Luis Gerardo (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Martín-Antonio, B (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Cibeira, María Teresa (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Bladé Creixenti, Juan (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Rosiñol, Laura (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Prat, Aleix (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Lozano, Ester (Universitat de Barcelona. Departament de Biologia Cel·lular, Fisiologia i Immunologia)
Fernández de Larrea, Carlos (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)

Date:	2021
Abstract:	Background: We previously reported algorithms based on clinical parameters and plasma cell characteristics to identify patients with smoldering multiple myeloma (SMM) with higher risk of progressing who could benefit from early treatment. In this work, we analyzed differences in the immune bone marrow (BM) microenvironment in SMM to better understand the role of immune surveillance in disease progression and to identify immune biomarkers associated to higher risk of progression. Methods: Gene expression analysis of BM cells from 28 patients with SMM, 22 patients with monoclonal gammopathy of undetermined significance (MGUS) and 22 patients with symptomatic MM was performed by using Nanostring Technology. Results: BM cells in SMM compared to both MGUS and symptomatic MM showed upregulation of genes encoding for key molecules in cytotoxicity. However, some of these cytotoxic molecules positively correlated with inhibitory immune checkpoints, which may impair the effector function of BM cytotoxic cells. Analysis of 28 patients with SMM revealed 4 distinct clusters based on immune composition and activation markers. Patients in cluster 2 showed a significant increase in expression of cytotoxic molecules but also inhibitory immune checkpoints compared to cluster 3, suggesting the presence of cytotoxic cells with an exhausted phenotype. Accordingly, patients in cluster 3 had a significantly longer progression free survival. Finally, individual gene expression analysis showed that higher expression of TNF superfamily members (TNF, TNFAIP3, TNFRSF14) was associated with shorter progression free survival. Conclusions: Our results suggest that exhausted cytotoxic cells are associated to high-risk patients with SMM. Biomarkers overexpressed in patients with this immune gene profile in combination with clinical parameters and PC characterization may be useful to identify SMM patients with higher risk of progression.
Grants:	Ministerio de Economía y Competitividad PI16/00423 Instituto de Salud Carlos III PI19/00669 Instituto de Salud Carlos III PI20/00436
Note:	Altres ajuts: This work was supported in part by Grants PI16/00423, PI19/ 00669 and PI20/00436 from Instituto de Salud Carlos III (Ministerio de Economía y Competitividad, co-funded by Fondo Europeo de Desarrollo Regional (FEDER)-Una manera de Hacer Europa) and the CERCA Programme/Generalitat de Catalunya.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Smoldering multiple myeloma ; Immunotherapy ; Immune checkpoints ; TIGIT ; Pronostic factors ; Bone marrow microenvironment
Published in:	Frontiers in immunology, Vol. 12 (22 2021) , p. 792609, ISSN 1664-3224

DOI: 10.3389/fimmu.2021.792609
PMID: 34880879

11 p, 6.7 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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