Aberrant single-cell phenotype and clinical implications of genotypically defined polyclonal plasma cells in myeloma
Abstract
Abstract Multiple myeloma (MM) is driven by clonal plasma cell (cPC)–intrinsic factors and changes in the tumor microenvironment (TME). To investigate whether residual polyclonal PCs (pPCs) are disrupted, single-cell (sc) RNA sequencing (scRNA-seq) and sc B-cell receptor analysis were applied in a cohort of 46 samples with PC dyscrasias and 21 healthy donors (HDs). Of 234 789 PCs, 64 432 were genotypically identified as pPCs with frequencies decreasing over different disease stages, from 23.66% in monoclonal gammopathy of undetermined significance to 3.23% in MMs (P = .00012). Both cPCs and pPCs had a comparable expression of typical lineage markers (ie, CD38 and CD138), whereas others were more variable (CD27 and ITGB7). Only cPCs overexpressed oncogenes (eg, CCND1/2 and NSD2), but CCND3 was often expressed in pPCs. B-cell maturation antigen was expressed on both pPCs and cPCs, whereas GPRC5D was mostly upregulated in cPCs with implications for on-target, off-tumor activity of targeted immunotherapies. In comparison with HDs, pPCs from patients showed upregulated autophagy and disrupted interaction with TME. Importantly, interferon-related pathways were significantly enriched in pPCs from patients vs HDs (adjusted P < .05) showing an inflamed phenotype affecting genotypically normal PCs. The function of pPCs was consequently affected and correlated with immunoparesis, driven by disrupted cellular interactions with TME. Leveraging our scRNA-seq data, we derived a “healthy PC signature” that could be applied to bulk transcriptomics from the CoMMpass data set and predicted significantly better progression-free survival and overall survival (log-rank P < .05 for both). Our findings show that genotypic sc identification of pPCs in PC dyscrasias has relevant pathogenic and clinical implications.
Article Details
Authors (30)
Matteo Claudio Da Vià
2Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Hematology Unit, Milan, Italy
Francesca Lazzaroni
2Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Antonio Matera
7University of Milan, Milano, Italy
Alessio Marella
7University of Milan, Milano, Italy
Akihiro Maeda
6Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
Claudio de Magistris
6Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
Loredana Pettine
16Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Antonio Giovanni Solimando
3Guido Baccelli Unit of Internal Medicine Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro” Medical School, Bari, Italy
Vanessa Desantis
4Section of Pharmacology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro Medical School, Bari, Italy
Giuseppe M. Peretti
5University Team of Regenerative and Reconstructive Orthopedics, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
Laura Mangiavini
5University Team of Regenerative and Reconstructive Orthopedics, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
Riccardo Giorgino
5University Team of Regenerative and Reconstructive Orthopedics, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
Sonia Fabris
2Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Stefania Pioggia
6Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
Alfredo Marchetti
1Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy
Marzia Barbieri
2Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Silvia Lonati
1Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy
Alessandra Cattaneo
3Flow Cytometry Laboratory, Clinical Pathology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Marta Tornese
3Flow Cytometry Laboratory, Clinical Pathology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Margherita Scopetti
1Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy
Emanuele Calvi
2Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Nayyer Latifinavid
2Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
Giancarlo Castellano
5Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Federica Torricelli
1Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
Antonino Neri
Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
Cathelijne Fokkema
1Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
Tom Cupedo
Erasmus MC Cancer Institute
Marta Lionetti
7University of Milan, Milano, Italy
Francesco Passamonti
University of Milan, Milan
Niccolò Bolli
1Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico