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 () and Michael Wang ()
Additional contact information
Shaojun Zhang: The University of Texas MD Anderson Cancer Center
Vivian Changying Jiang: The University of Texas MD Anderson Cancer Center
Guangchun Han: The University of Texas MD Anderson Cancer Center
Dapeng Hao: The University of Texas MD Anderson Cancer Center
Junwei Lian: The University of Texas MD Anderson Cancer Center
Yang Liu: The University of Texas MD Anderson Cancer Center
Qingsong Cai: The University of Texas MD Anderson Cancer Center
Rongjia Zhang: The University of Texas MD Anderson Cancer Center
Joseph McIntosh: The University of Texas MD Anderson Cancer Center
Ruiping Wang: The University of Texas MD Anderson Cancer Center
Minghao Dang: The University of Texas MD Anderson Cancer Center
Enyu Dai: The University of Texas MD Anderson Cancer Center
Yuanxin Wang: The University of Texas MD Anderson Cancer Center
David Santos: The University of Texas MD Anderson Cancer Center
Maria Badillo: The University of Texas MD Anderson Cancer Center
Angela Leeming: The University of Texas MD Anderson Cancer Center
Zhihong Chen: The University of Texas MD Anderson Cancer Center
Kimberly Hartig: The University of Texas MD Anderson Cancer Center
John Bigcal: The University of Texas MD Anderson Cancer Center
Jia Zhou: The University of Texas Medical Branch
Rashmi Kanagal-Shamanna: The University of Texas MD Anderson Cancer Center
Chi Young Ok: The University of Texas MD Anderson Cancer Center
Hun Lee: The University of Texas MD Anderson Cancer Center
Raphael E. Steiner: The University of Texas MD Anderson Cancer Center
Jianhua Zhang: The University of Texas MD Anderson Cancer Center
Xingzhi Song: The University of Texas MD Anderson Cancer Center
Ranjit Nair: The University of Texas MD Anderson Cancer Center
Sairah Ahmed: The University of Texas MD Anderson Cancer Center
Alma Rodriquez: The University of Texas MD Anderson Cancer Center
Selvi Thirumurthi: The University of Texas MD Anderson Cancer Center
Preetesh Jain: The University of Texas MD Anderson Cancer Center
Nicolaus Wagner-Bartak: The University of Texas MD Anderson Cancer Center
Holly Hill: The University of Texas MD Anderson Cancer Center
Krystle Nomie: The University of Texas MD Anderson Cancer Center
Christopher Flowers: The University of Texas MD Anderson Cancer Center
Andrew Futreal: The University of Texas MD Anderson Cancer Center
Linghua Wang: The University of Texas MD Anderson Cancer Center
Michael Wang: The University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 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.

Date: 2021
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DOI: 10.1038/s41467-021-22872-z

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