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- Title
Longitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma.
- Authors
Zhang, Shaojun; Jiang, Vivian Changying; Han, Guangchun; Hao, Dapeng; Lian, Junwei; Liu, Yang; Zhang, Rongjia; McIntosh, Joseph; Wang, Ruiping; Dang, Minghao; Dai, Enyu; Wang, Yuanxin; Santos, David; Badillo, Maria; Leeming, Angela; Chen, Zhihong; Hartig, Kimberly; Bigcal, John; Zhou, Jia; Kanagal-Shamanna, Rashmi
- 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. Mantle cell lymphoma can be refractory to treatment. Here, the authors used single cell sequencing to study the tumours of patients that were responsive and resistant to treatment and find gains of 17q in resistant tumours, which they attribute to increased expression of Birc5 and validate these findings in mouse models of the disease.
- Subjects
MANTLE cell lymphoma; LABORATORY mice; HETEROGENEITY; ANIMAL models in research
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-22872-z