Endothelial cell–leukemia interactions remodel drug responses, uncovering T-ALL vulnerabilities

• Published in: Blood Vol. 141; no. 5; pp. 503 - 518
• Main Authors: Cappelli, Luca Vincenzo, Fiore, Danilo, Phillip, Jude M., Yoffe, Liron, Di Giacomo, Filomena, Chiu, William, Hu, Yang, Kayembe, Clarisse, Ginsberg, Michael, Consolino, Lorena, Barcia Duran, Jose Gabriel, Zamponi, Nahuel, Melnick, Ari M., Boccalatte, Francesco, Tam, Wayne, Elemento, Olivier, Chiaretti, Sabina, Guarini, Anna, Foà, Robin, Cerchietti, Leandro, Rafii, Shahin, Inghirami, Giorgio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.02.2023; The American Society of Hematology
• Subjects: Cell Communication; Coculture Techniques; Endothelial Cells - metabolism; Humans; Lymphoid Neoplasia; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Tumor Microenvironment
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2022015414

•We identified active compounds in a library of 22 T-ALL PDX and discovered public and private vulnerabilities•Interacting ECs and T-ALL underwent reciprocal transcriptomic changes [Display omitted] T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and often incurable disease. To uncover therapeutic vulnerabilities, we first developed T-ALL patient–derived tumor xenografts (PDXs) and exposed PDX cells to a library of 433 clinical-stage compounds in vitro. We identified 39 broadly active drugs with antileukemia activity. Because endothelial cells (ECs) can alter drug responses in T-ALL, we developed an EC/T-ALL coculture system. We found that ECs provide protumorigenic signals and mitigate drug responses in T-ALL PDXs. Whereas ECs broadly rescued several compounds in most models, for some drugs the rescue was restricted to individual PDXs, suggesting unique crosstalk interactions and/or intrinsic tumor features. Mechanistically, cocultured T-ALL cells and ECs underwent bidirectional transcriptomic changes at the single-cell level, highlighting distinct “education signatures.” These changes were linked to bidirectional regulation of multiple pathways in T-ALL cells as well as in ECs. Remarkably, in vitro EC-educated T-ALL cells transcriptionally mirrored ex vivo splenic T-ALL at single-cell resolution. Last, 5 effective drugs from the 2 drug screenings were tested in vivo and shown to effectively delay tumor growth and dissemination thus prolonging overall survival. In sum, we developed a T-ALL/EC platform that elucidated leukemia-microenvironment interactions and identified effective compounds and therapeutic vulnerabilities. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease that is supported by the tumor microenvironment. Cappelli and colleagues used primary T-ALL patient cells cocultured with endothelial cells (ECs) to delineate the role of ECs in chemoprotection of T-ALL cells and to screen for drugs to overcome that resistance. The authors identified 5 agents that improve survival in mouse xenografts, suggesting that the platform can be used to identify compounds that target tumor cell–EC interactions.