TY - JOUR
T1 - Longitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma
AU - Zhang, Shaojun
AU - Jiang, Vivian Changying
AU - Han, Guangchun
AU - Hao, Dapeng
AU - Lian, Junwei
AU - Liu, Yang
AU - Zhang, Rongjia
AU - McIntosh, Joseph
AU - Wang, Ruiping
AU - Dang, Minghao
AU - Dai, Enyu
AU - Wang, Yuanxin
AU - Santos, David
AU - Badillo, Maria
AU - Leeming, Angela
AU - Chen, Zhihong
AU - Hartig, Kimberly
AU - Bigcal, John
AU - Zhou, Jia
AU - Kanagal-Shamanna, Rashmi
AU - Ok, Chi Young
AU - Lee, Hun
AU - Steiner, Raphael E.
AU - Zhang, Jianhua
AU - Song, Xingzhi
AU - Nair, Ranjit
AU - Ahmed, Sairah
AU - Rodriquez, Alma
AU - Thirumurthi, Selvi
AU - Jain, Preetesh
AU - Wagner-Bartak, Nicolaus
AU - Hill, Holly
AU - Nomie, Krystle
AU - Flowers, Christopher
AU - Futreal, Andrew
AU - Wang, Linghua
AU - Wang, Michael
N1 - Funding Information:
We thank the patients and their families who contributed to this research study. This study was supported by the generous philanthropic funds from The Gary Rogers Foundation, Kinder Foundation, and the Cullen Foundation, and the start-up research fund kindly provided to L. Wang by MD Anderson Cancer Center. This study was also supported by the NIH-funded Cancer Center Support Grant (CCSG) P30 CA016672 (Peter Pisters, Principal Investigator) and the NIH Core Grant for the Sequencing and Microarray Facility (CA016672). We thank Dr. Adam for her critical editing of the paper. The Advanced Cytometry & Sorting Core Facility is supported by NCI P30CA016672.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-22872-z
DO - 10.1038/s41467-021-22872-z
M3 - Article
C2 - 34001881
AN - SCOPUS:85106213315
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2877
ER -