NSGS mice humanized with cord blood mononuclear cells show sustained and functional myeloid-lymphoid representation with limited graft-versus-host disease
Panisello, Carla (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Aschero, Rosario (Institut de Recerca Sant Joan de Déu)
Martnez-Moreno, Alba (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Roca Ho, Heleia (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Falgàs, Aïda (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
González-Navarro, Europa Azucena (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Carabelli, Julieta (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Pradenas, Edwards (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Lázaro-Díez, María (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Prado, Julia G.. (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Blanco, Julià (Universitat Autònoma de Barcelona)
Carrillo, Jorge (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Juan, Manel (August Pi i Sunyer Institute of Biomedical Research)
Carcaboso, Angel M (Institut de Recerca Sant Joan de Déu)
Bueno, Clara (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Menéndez, Pablo (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)

Fecha:	2024
Resumen:	Humanized immunodeficient mice serve as critical models for investigating the functional interplay between transplanted human cells and a pre-reconstituted human immune system. These models facilitate the study of molecular and cellular pathogenic mechanisms and enable the evaluation of the efficacy and toxicity of immunotherapies, thereby accelerating their preclinical and clinical development. Current strategies rely on inefficient, long-term/delayed hematopoietic reconstitution by CD34+ hematopoietic progenitors or short-term reconstitution with peripheral blood mononuclear cells (PB-MNCs) associated with high rates of graft-versus-host disease (GvHD) and an inefficient representation of immune cell populations. Here, we hypothesized that immunologically naïve cord blood mononuclear cells (CB-MNCs) could serve as a superior alternative, providing long-lasting and functionally effective immune reconstitution. We conducted a comprehensive comparison between the non-obese diabetic (NOD). Cg-Prkdc∧ˆscid-IL2rg∧ˆtm1Wjl/SzJ (NSG) and NSG-Tg(CMV-IL3,CSF2,KITLG)∧ˆ1Eav/MloySzJ (NSGS) immunodeficient mouse models following humanization with either PB-MNCs or CB-MNCs. We assessed the engraftment dynamics of various human immune cells over time and monitored the development of GvHD in both models. For the most promising model, we extensively evaluated immune cell functionality in vitro and in vivo using sarcoma and leukemia xenografts. Humanizing NSGS mice with CB-MNCs results in a rapid, robust, and sustained representation of a diverse range of functional human lymphoid and myeloid cell populations while minimizing GvHD incidence. In this model, human immune cell populations significantly impair the growth and engraftment of sarcoma and B-cell acute lymphoblastic leukemia cells, with a significant inverse correlation between immune cell levels and tumor growth. This study establishes a fast, efficient, and reliable in vivo platform for various applications in cancer immunotherapy, particularly for exploring the complex interactions between cancer cells, immune cells, and the tumor microenvironment in vivo, prior to clinical development.
Ayudas:	Agencia Estatal de Investigación PLEC2022-009416 "la Caixa" Foundation CI21-00189 European Commission 101100665
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Engraftment ; Immunotherapy ; Solid tumor ; Tumor microenvironment - TME ; Graft versus leukemia
Publicado en:	Journal for immunotherapy of cancer, Vol. 12 (october 2024) , ISSN 2051-1426

DOI: 10.1136/jitc-2024-009198
PMID: 39379097

9 p, 2.6 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Instituto de Investigación contra la Leucemia Josep Carreras
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