STROMAL CELLS ENGINEERED TO EXPRESS T CELL FACTORS INDUCE ROBUST CLL CELL PROLIFERATION IN VITRO AND IN PDX COTRANSPLANTATIONS ALLOWING THE IDENTIFICATION OF ANTI-PROLIFERATIVE DRUGS

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F24%3A00137865" target="_blank" >RIV/00216224:14740/24:00137865 - isvavai.cz</a>

Result on the web

<a href="https://www.hematology2024.cz/" target="_blank" >https://www.hematology2024.cz/</a>

DOI - Digital Object Identifier

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Result language

angličtina

Original language name

STROMAL CELLS ENGINEERED TO EXPRESS T CELL FACTORS INDUCE ROBUST CLL CELL PROLIFERATION IN VITRO AND IN PDX COTRANSPLANTATIONS ALLOWING THE IDENTIFICATION OF ANTI-PROLIFERATIVE DRUGS

Original language description

Several in vitro models have been developed to mimic CLL proliferation in immune niches; however, they typically do not induce robust proliferation. We prepared a novel model based on mimicking T-cell signals. Six supportive cell lines were prepared by engineering HS5 stromal cells with stable expression of human CD40L, IL4, IL21, and their combinations. Co-culture with HS5 expressing CD40L and IL4 led to mild CLL cell proliferation (median 7% at day 7), while the HS5 expressing CD40L, IL4, and IL21 led to unprecedented proliferation rate of 44%, which is higher and more reproducible then in other available models. The co-cultures mimicked the gene expression fingerprint of lymph node CLL cells (MYC, NFkB, and E2F signatures; as defined by Herishanu et al, 2011). The other induced pathways reveal novel CLL vulnerabilities in context of CLL-T cell-induced proliferation, and we tested 10 inhibitors based on these data. This revealed for the first time that RAF inhibitors and FOXO1 inhibitors block CLL proliferation. The co-culture model can be downscaled to five microliter volume for large drug screening purposes or upscaled to CLL PDXs by HS5-CD40L-IL4±IL21 co-transplantation. We co-transplanted 41 NSG mice with CLL cells and HS5-CD40L-IL4 or HS5-CD40L-IL4-IL21 using a subcutaneous scaffold and intraperitoneal injection leading to 47% or 82% engraftment efficacy, respectively, with ~20% of PDXs being clonally related to CLL. This shows that CLL cell engraftment in NSG mice can be supported by engineered HS5 cells, thus bypassing the need to use primary T cells in PDX (Bagnara et al, 2011).

Czech name

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Czech description

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Type

O - Miscellaneous

CEP classification

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OECD FORD branch

30204 - Oncology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů