Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity
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...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001419.full |
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| author | Samanta Romina Zanetti Paola Alejandra Romecin Meritxell Vinyoles Manel Juan José Luis Fuster Mireia Cámos Sergi Querol Mario Delgado Pablo Menendez |
| author_facet | Samanta Romina Zanetti Paola Alejandra Romecin Meritxell Vinyoles Manel Juan José Luis Fuster Mireia Cámos Sergi Querol Mario Delgado Pablo Menendez |
| author_sort | Samanta Romina Zanetti |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-00d6738a7e084a4683174f186e16f2eb |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-00d6738a7e084a4683174f186e16f2eb2024-11-10T00:50:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-001419Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activitySamanta Romina Zanetti0Paola Alejandra Romecin1Meritxell Vinyoles2Manel Juan3José Luis Fuster4Mireia Cámos5Sergi Querol6Mario Delgado7Pablo Menendez81 Josep Carreras Leukemia Research Institute, Barcelona, Spain1 Josep Carreras Leukemia Research Institute, Barcelona, Spain1 Josep Carreras Leukemia Research Institute, Barcelona, SpainRed Española de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain3 Sección de Oncohematología Pediátrica, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain7 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain8 Blood and Tissue Bank, Barcelona, Spain9 Instituto de Parasitología y Biomedicina López-Neyra-CSIC, Barcelona, Spain11 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), ISCIII, Barcelona, SpainBackground 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.https://jitc.bmj.com/content/8/2/e001419.full |
| spellingShingle | Samanta Romina Zanetti Paola Alejandra Romecin Meritxell Vinyoles Manel Juan José Luis Fuster Mireia Cámos Sergi Querol Mario Delgado Pablo Menendez Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity Journal for ImmunoTherapy of Cancer |
| title | Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity |
| title_full | Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity |
| title_fullStr | Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity |
| title_full_unstemmed | Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity |
| title_short | Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity |
| title_sort | bone marrow msc from pediatric patients with b all highly immunosuppress t cell responses but do not compromise cd19 car t cell activity |
| url | https://jitc.bmj.com/content/8/2/e001419.full |
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