Nature Communications (May 2021)
Longitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma
- Shaojun Zhang,
- Vivian Changying Jiang,
- Guangchun Han,
- Dapeng Hao,
- Junwei Lian,
- Yang Liu,
- Qingsong Cai,
- Rongjia Zhang,
- Joseph McIntosh,
- Ruiping Wang,
- Minghao Dang,
- Enyu Dai,
- Yuanxin Wang,
- David Santos,
- Maria Badillo,
- Angela Leeming,
- Zhihong Chen,
- Kimberly Hartig,
- John Bigcal,
- Jia Zhou,
- Rashmi Kanagal-Shamanna,
- Chi Young Ok,
- Hun Lee,
- Raphael E. Steiner,
- Jianhua Zhang,
- Xingzhi Song,
- Ranjit Nair,
- Sairah Ahmed,
- Alma Rodriquez,
- Selvi Thirumurthi,
- Preetesh Jain,
- Nicolaus Wagner-Bartak,
- Holly Hill,
- Krystle Nomie,
- Christopher Flowers,
- Andrew Futreal,
- Linghua Wang,
- Michael Wang
Affiliations
- Shaojun Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Vivian Changying Jiang
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Guangchun Han
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Dapeng Hao
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Junwei Lian
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Yang Liu
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Qingsong Cai
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Rongjia Zhang
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Joseph McIntosh
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Ruiping Wang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Minghao Dang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Enyu Dai
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Yuanxin Wang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- David Santos
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center
- Maria Badillo
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Angela Leeming
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Zhihong Chen
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Kimberly Hartig
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- John Bigcal
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Jia Zhou
- Department of Pharmacology and Toxicology, The University of Texas Medical Branch
- Rashmi Kanagal-Shamanna
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center
- Chi Young Ok
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center
- Hun Lee
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Raphael E. Steiner
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Jianhua Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Xingzhi Song
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Ranjit Nair
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Sairah Ahmed
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Alma Rodriquez
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Selvi Thirumurthi
- Department of Gastroenterology, Hepathology & Nutrition, The University of Texas MD Anderson Cancer Center
- Preetesh Jain
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Nicolaus Wagner-Bartak
- Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center
- Holly Hill
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Krystle Nomie
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Christopher Flowers
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Linghua Wang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
- Michael Wang
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center
- DOI
- https://doi.org/10.1038/s41467-021-22872-z
- Journal volume & issue
-
Vol. 12,
no. 1
pp. 1 – 17
Abstract
Abstract The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. We characterize the cellular and molecular heterogeneity within and across patients and delineate the dynamic evolution of tumor and immune cell compartments at single cell resolution in longitudinal specimens from ibrutinib-sensitive patients and non-responders. Temporal activation of multiple cancer hallmark pathways and acquisition of 17q are observed in a refractory MCL. Multi-platform validation is performed at genomic and cellular levels in PDX models and larger patient cohorts. We demonstrate that due to 17q gain, BIRC5/survivin expression is upregulated in resistant MCL tumor cells and targeting BIRC5 results in marked tumor inhibition in preclinical models. In addition, we discover notable differences in the tumor microenvironment including progressive dampening of CD8+ T cells and aberrant cell-to-cell communication networks in refractory MCLs. This study reveals diverse and dynamic tumor and immune programs underlying therapy resistance in MCL.
