期刊
JOURNAL FOR IMMUNOTHERAPY OF CANCER
卷 8, 期 2, 页码 -出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2020-001419
关键词
cell engineering; immunotherapy; inflammation; tumor microenvironment; immunomodulation
资金
- European Research Council [CoG-2014-646903, PoC-2018-811220]
- Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2016--80481R]
- Fundacion Uno entre Cienmil
- Obra Social La Caixa [LCF/PR/HR19/52160011]
- Leo Messi Foundation
- 'Heroes hasta la medula' initiative
- Marie Sklodowska Curie Fellowship [GA 795833]
- Juan de la Cierva fellowship from the MINECO
Background Although adoptive transfer of CD19-directed chimeric antigen receptor (CAR) T-cells (CD19-CAR T-cells) achieves high rates of complete response in patients with B-cell acute lymphoblastic leukemia (B-ALL), relapse is common. Bone marrow (BM) mesenchymal stem/stromal cells (BM-MSC) are key components of the hematopoietic niche and are implicated in B-ALL pathogenesis and therapy resistance. MSC exert an immunosuppressive effect on T-cells; however, their impact on CD19-CAR T-cell activity is understudied. Methods We performed a detailed characterization of BM-MSC from pediatric patients with B-ALL (B-ALL BM-MSC), evaluated their immunomodulatory properties and their impact on CD19-CAR T-cell activity in vitro using microscopy, qRT-PCR, ELISA, flow cytometry analysis and in vivo using a preclinical model of severe colitis and a B-ALL xenograft model. Results While B-ALL BM-MSC were less proliferative than those from age-matched healthy donors (HD), the morphology, immunophenotype, differentiation potential and chemoprotection was very similar. Likewise, both BM-MSC populations were equally immunosuppressive in vitro and anti-inflammatory in an in vivo model of severe colitis. Interestingly, BM-MSC failed to impair CD19-CAR T-cell cytotoxicity or cytokine production in vitro using B-ALL cell lines and primary B-ALL cells. Finally, the growth of NALM6 cells was controlled in vivo by CD19-CAR T-cells irrespective of the absence/presence of BM-MSC. Conclusions Collectively, our data demonstrate that pediatric B-ALL and HD BM-MSC equally immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity.
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