Longitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma

Shaojun Zhang,Sairah Ahmed,Hun Lee,Andrew Futreal,David M Cordas Dos Santos ,Rashmi Kanagal‐Shamanna ,Maria Badillo,Rongjia Zhang,Ruiping Wang,Joseph Mcintosh,Raphaël Steiner ,John Bigcal,Selvi Thirumurthi,Linghua Wang,Holly A Hill ,Chi Young Ok,Ranjit Nair,Xingzhi Song,Yang Liu,Angela Leeming,Jiamei Lian ,Preetesh Jain,Krystle Nomie,Nicolaus A Wagner‐Bartak ,Enyu Dai,Minghao Dang,Jia Zhou,Christopher R Flowers ,Changying Jiang ,Guangchun Han,Alma Rodriquez,Zhihong Chen,Yuanxin Wang,Kimberly Hartig,Jianhua Zhang,Dapeng Hao,Michael Wang

doi:10.1038/s41467-021-22872-z

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.

Highlights

The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood
Patient C presented with leukemic MCL with lymphadenopathies involving multiple compartments including bone marrow (BM) involvement (55%) but without splenomegaly
Patient B was diagnosed as stage IV MCL with splenomegaly and multiplecompartment lymphadenopathies, peripheral blood (PB) (70%), and BM (33%) involvement

Summary

Introduction

The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. Recent work by our group identified genomic and transcriptomic alterations in resistant MCL cells, including metabolic reprogramming toward glutamine-fueled oxidative phosphorylation (OXPHOS) that drives ibrutinib resistance in MCL15. These studies were centered on bulk analysis, and the single-cell landscape and roles of individual cell populations, such as tumor and immune cell subsets and their dynamic interactions, in therapeutic resistance and evolution of MCL, has not been systematically characterized. Longitudinal tracking of clonal heterogeneity and evolution of the complex tumor ecosystems can advance our understanding of how diverse tumor and immune programs drive therapy resistance and inform novel therapeutic strategies. We dissect the dynamic multicellular tumor “ecosystem” using the cutting-edge single-cell transcriptome sequencing (scRNA-seq) technology, coupled with longitudinal sampling and deep molecular profiling to understand refractory MCL at an exceptional resolution

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Results

Conclusion