Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia

Matthew T Witkowski; Igor Dolgalev; Nikki A Evensen; Chao Ma; Tiffany Chambers; Kathryn G Roberts; Sheetal Sreeram; Yuling Dai; Anastasia N Tikhonova; Audrey Lasry; Chunxu Qu; Deqing Pei; Cheng Cheng; Gabriel A Robbins; Joanna Pierro; Shanmugapriya Selvaraj; Valeria Mezzano; Marla Daves; Philip J Lupo; Michael E Scheurer; Cynthia A Loomis; Charles G Mullighan; Weiqiang Chen; Karen R Rabin; Aristotelis Tsirigos; William L Carroll; Iannis Aifantis

doi:10.1016/j.ccell.2020.04.015

Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia

Cancer Cell. 2020 Jun 8;37(6):867-882.e12. doi: 10.1016/j.ccell.2020.04.015. Epub 2020 May 28.

Authors

Matthew T Witkowski¹, Igor Dolgalev², Nikki A Evensen³, Chao Ma⁴, Tiffany Chambers⁵, Kathryn G Roberts⁶, Sheetal Sreeram³, Yuling Dai³, Anastasia N Tikhonova³, Audrey Lasry³, Chunxu Qu⁶, Deqing Pei⁶, Cheng Cheng⁶, Gabriel A Robbins³, Joanna Pierro³, Shanmugapriya Selvaraj⁷, Valeria Mezzano⁷, Marla Daves⁵, Philip J Lupo⁵, Michael E Scheurer⁵, Cynthia A Loomis⁷, Charles G Mullighan⁶, Weiqiang Chen⁴, Karen R Rabin⁵, Aristotelis Tsirigos², William L Carroll⁸, Iannis Aifantis⁹

Affiliations

¹ Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Laura & Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA. Electronic address: [email protected].
² Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Laura & Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Applied Bioinformatics Laboratories, New York University School of Medicine, New York, NY 10016, USA.
³ Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Laura & Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
⁴ Department of Mechanical and Aerospace Engineering, New York University, New York, NY 11202, USA; Department of Biomedical Engineering, New York University, New York, NY 11202, USA.
⁵ Division of Pediatric Hematology/Oncology, College of Medicine, Baylor University, Houston, TX 77030, USA.
⁶ Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁷ Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Experimental Pathology Research Laboratory, New York University School of Medicine, New York, NY 10016, USA.
⁸ Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Laura & Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA. Electronic address: [email protected].
⁹ Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Laura & Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA. Electronic address: [email protected].

Abstract

A subset of B cell acute lymphoblastic leukemia (B-ALL) patients will relapse and succumb to therapy-resistant disease. The bone marrow microenvironment may support B-ALL progression and treatment evasion. Utilizing single-cell approaches, we demonstrate B-ALL bone marrow immune microenvironment remodeling upon disease initiation and subsequent re-emergence during conventional chemotherapy. We uncover a role for non-classical monocytes in B-ALL survival, and demonstrate monocyte abundance at B-ALL diagnosis is predictive of pediatric and adult B-ALL patient survival. We show that human B-ALL blasts alter a vascularized microenvironment promoting monocytic differentiation, while depleting leukemia-associated monocytes in B-ALL animal models prolongs disease remission in vivo. Our profiling of the B-ALL immune microenvironment identifies extrinsic regulators of B-ALL survival supporting new immune-based therapeutic approaches for high-risk B-ALL treatment.

Keywords: acute lymphoblastic leukemia; chemotherapy; immune microenvironment; monocytes; relapse; single cell.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Animals
Antineoplastic Agents / pharmacology
Bone Marrow Transplantation
Case-Control Studies
Child
Child, Preschool
Female
Humans
Infant
Male
Mice, Inbred C57BL
Monocytes / immunology*
Neoplasm Recurrence, Local / immunology*
Neoplasm Recurrence, Local / pathology
Neoplasm Recurrence, Local / therapy
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / immunology*
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / therapy
Prognosis
Proteome / analysis
RNA-Seq
Retrospective Studies
Single-Cell Analysis
Survival Rate
Tumor Microenvironment / immunology*
Young Adult

Substances

Antineoplastic Agents
Proteome

Abstract

Publication types

MeSH terms

Substances

Grants and funding