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

Abstract

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 (PDX) and exposed PDX cells to a library of 433 clinical-stage compounds in vitro. We identified 39 broadly active compounds with anti-leukemia activity. Since endothelial cells (ECs) can alter drug responses in T-ALL, we developed an endothelial cells (ECs) / T-ALL co-culture system. We found that ECs provide pro-tumorigenic signals and mitigate drug responses to individual T-ALL PDX. ECs broadly rescued several compounds in most of the models, while other drugs were rescued only in individual PDXs suggesting unique crosstalk interactions and/or intrinsic tumor features. Mechanistically, co-cultured T-ALL and ECs underwent bi-directional transcriptomic changes at the single-cell level, highlighting distinct "education signatures". These changes were linked to a bi-directional regulation of multiple pathways in T-ALL and ECs. Remarkably, in-vitro EC-educated T-ALL cells mirrored ex-vivo splenic T-ALL at the single-cell resolution. Lastly, five effective drugs from the two drug screenings were tested in vivo and shown to effectively delay tumor growth/dissemination and prolonging the overall survival (OS). We anticipate that this T-ALL-EC platform can contribute to elucidating leukemia-microenvironment interactions and identify effective compounds and therapeutic vulnerabilities.

Nanotechnology-based diagnostics and therapeutics in acute lymphoblastic leukemia: a systematic review of preclinical studies

“…Besides, routine CNS prophylaxis is proposed, and allogeneic hematopoietic stem cell transplantation (Allo-HSCT) stands as the standard consolidation treatment in high-risk patients with an available donor. 7–11 If not treated, the leukemic cells are distributed to the blood circulation system and subsequently to vital body organs. Moreover, liquid tumors, such as leukemia, cannot be surgically removed, unlike solid tumors.…”

“…Acute lymphocytic leukemia (ALL) is a kind of leukemia that develops when lymphocytes in bone marrow (BM) proliferate abnormally. [1][2][3][4][5][6][7][8] It is divided into two types based on the cell of origin: B-ALL and T-ALL. There are four stages of the treatment for ALL, which usually take two to three years: induction, consolidation, intensication, and long-term maintenance.…”

“…Besides, routine CNS prophylaxis is proposed, and allogeneic hematopoietic stem cell transplantation (Allo-HSCT) stands as the standard consolidation treatment in high-risk patients with an available donor. [7][8][9][10][11] If not treated, the leukemic cells are a Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientic Education and Research Network (USERN), Tehran, Iran. E-mail: khademi.1358@ yahoo.com b Immunology Board for Transplantation and Cell-Based Therapeutics (Immuno_TACT), Universal Scientic Education and Research Network (USERN), Tehran, Iran distributed to the blood circulation system and subsequently to vital body organs.…”

Immune and stromal transcriptional patterns that influence the outcome of classic Hodgkin Lymphoma

“…These results strengthen evidence of dynamic crosstalk between tumor-associated endothelial cells and cancer cells regulating tumor aggressiveness. 50 We have also reported that COX-2 expression was an unfavorable prognostic factor in cHL. 44 Dual inhibition of COX-2 and VEGF pathways reduced tumor metastasis and extended overall survival in several in vivo cancer models.…”

Decoding leukemia at the single-cell level: clonal architecture, classification, microenvironment, and drug resistance

“…First developed a T-ALL/EC platform that can help elucidate the leukemia-microenvironment interactions with endothelial cells. [ 117 ] …”