Single Cell Analysis of the Tumor Microenvironment Landscape Across the Disease Spectrum of Multiple Myeloma
Abstract
Multiple myeloma progresses from precursor states to active disease, and studying tumor microenvironment (TME) evolution across these stages is key to understanding immune dysregulation and therapeutic resistance. Here, we integrated paired single-cell RNA, T-, and B-cell receptor sequencing data from bone marrow samples of 235 patients spanning the disease spectrum. This dataset revealed dynamic changes in the abundance and functional states of diverse immune populations, including T-, natural killer, B-, and myeloid cells. Using non-negative factorization of cell-subset composition, we identified five reproducible TME subtypes, or "ecotypes," defined by coordinated cellular architectures. These ecotypes captured structured variation beyond disease stage and were associated with distinct cell-cell communication networks, cytokine signaling landscapes, transcription factor programs, and shared gene modules, reflecting coordinated immune adaptation to microenvironmental constraints. By linking tumor features with immune changes and ecotype distributions, we identified context-dependent associations influenced by both disease biology and treatment effects on the TME. We found that an ecotype enriched for bone marrow-resident populations and limited immune infiltration was associated with tumor expansion and inferior clinical outcomes, whereas ecotypes reflecting T-cell functional states showed distinct associations with immunotherapy response and survival. Our study provides a comprehensive single-cell immune atlas of multiple myeloma and its precursors, offering insights into TME organization and progression, and may guide development of stage-specific or ecotype-targeted immunotherapies.
Article Details
Authors (30)
Minghao Dang
Luz Yurany Moreno Rueda
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Maria Jose Acevedo Calado
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Hima Bansal
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
David Alejandro Berrios Nolasco
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Amishi U Vora
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Jonathan D Mejia
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Mei Huang
Wei Tan
Li Qin
Yunhe Liu
Yang Liu
David E. Mery
University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
Yan Cheng
Key Laboratory of Polar Materials and Devices (MOE), School of Information and Electronic Engineering (School of Integrated Circuits Science and Engineering), East China Normal University, Shanghai, China.
Fenghuang Zhan
University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
John D. Shaughnessy
University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
Qing Yi
Pei Lin
Mahmoud R. Gaballa
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Oren Pasvolsky
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Hans C. Lee
1Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
Sheeba K. Thomas
M.D. Anderson Cancer Center, Houston, Texas, United States
Donna M Weber
University of Texas, Houston, Texas, United States
Krina K. Patel
The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States
Melody R Becnel
MD Anderson Cancer Center, houston, Texas, United States
Jing Christine Ye
M.D. Anderson Cancer Center, University of Texas, Houston
Isere Kuiatse
The University of Texas M. D. Anderson Cancer Center
Elisabet E Manasanch
Regeneron Pharmaceuticals, Warren, New Jersey, United States
Linghua Wang
Robert Z. Orlowski
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States