Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma

Oksana Zavidij; Nicholas J Haradhvala; Tarek H Mouhieddine; Romanos Sklavenitis-Pistofidis; Songjie Cai; Mairead Reidy; Mahshid Rahmat; Abdallah Flaifel; Benjamin Ferland; Nang K Su; Michael P Agius; Jihye Park; Salomon Manier; Mark Bustoros; Daisy Huynh; Marzia Capelletti; Brianna Berrios; Chia-Jen Liu; Meng Xiao He; Esteban Braggio; Rafael Fonseca; Yosef E Maruvka; Jennifer L Guerriero; Melissa Goldman; Eliezer M Van Allen; Steven A McCarroll; Jamil Azzi; Gad Getz; Irene M Ghobrial

doi:10.1038/s43018-020-0053-3

Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma

Nat Cancer. 2020 May;1(5):493-506. doi: 10.1038/s43018-020-0053-3. Epub 2020 Apr 27.

Authors

Oksana Zavidij^#^{1

2

3}, Nicholas J Haradhvala^#^{3

4

5}, Tarek H Mouhieddine^#^{1

2

3}, Romanos Sklavenitis-Pistofidis^{1

2

3}, Songjie Cai^{2

6}, Mairead Reidy^{1

2

3}, Mahshid Rahmat^{1

2

3}, Abdallah Flaifel^{2

7}, Benjamin Ferland⁷, Nang K Su¹, Michael P Agius^{1

2

3}, Jihye Park^{1

2

3}, Salomon Manier^{1

2}, Mark Bustoros^{1

2

3}, Daisy Huynh¹, Marzia Capelletti^{1

2

3}, Brianna Berrios¹, Chia-Jen Liu^{1

2}, Meng Xiao He^{3

5}, Esteban Braggio⁸, Rafael Fonseca⁸, Yosef E Maruvka³, Jennifer L Guerriero^{1

2}, Melissa Goldman^{2

3}, Eliezer M Van Allen^{1

2

3}, Steven A McCarroll^{2

3}, Jamil Azzi^{2

6}, Gad Getz^{9

10

11}, Irene M Ghobrial^{12

13

14}

Affiliations

¹ Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
² Harvard Medical School, Boston, MA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Massachusetts General Hospital, Boston, MA, USA.
⁵ Harvard Biophysics Graduate Program, Harvard University, Boston, MA, USA.
⁶ Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Boston, MA, USA.
⁷ Specialized Histopathology Core, Brigham and Women's Hospital, Boston, MA, USA.
⁸ Department of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA.
⁹ Harvard Medical School, Boston, MA, USA. gadgetz@broadinstitute.org.
¹⁰ Broad Institute of MIT and Harvard, Cambridge, MA, USA. gadgetz@broadinstitute.org.
¹¹ Massachusetts General Hospital, Boston, MA, USA. gadgetz@broadinstitute.org.
¹² Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. irene_ghobrial@dfci.harvard.edu.
¹³ Harvard Medical School, Boston, MA, USA. irene_ghobrial@dfci.harvard.edu.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA. irene_ghobrial@dfci.harvard.edu.

^# Contributed equally.

Abstract

Precursor states of Multiple Myeloma (MM) and its native tumor microenvironment need in-depth molecular characterization to better stratify and treat patients at risk. Using single-cell RNA sequencing of bone marrow cells from precursor stages, MGUS and smoldering myeloma (SMM), to full-blown MM alongside healthy donors, we demonstrate early immune changes during patient progression. We find NK cell abundance is frequently increased in early stages, and associated with altered chemokine receptor expression. As early as SMM, we show loss of GrK⁺ memory cytotoxic T-cells, and show their critical role in MM immunosurveillance in mouse models. Finally, we report MHC class II dysregulation in CD14⁺ monocytes, which results in T cell suppression in vitro. These results provide a comprehensive map of immune changes at play over the evolution of pre-malignant MM, which will help develop strategies for immune-based patient stratification.

Keywords: MGUS; SMM; immune microenvironment; multiple myeloma; plasma cells; single-cell RNA sequencing; tumor microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
Mice
Monoclonal Gammopathy of Undetermined Significance* / genetics
Multiple Myeloma* / genetics
Sequence Analysis, RNA
Smoldering Multiple Myeloma*
Tumor Microenvironment / genetics

Abstract

Publication types

MeSH terms

Grants and funding