Mesenchymal stem cells derived from low risk acute lymphoblastic leukemia patients promote NK cell antitumor activity.
Mesenchymal stem cells (MSCs) are key components of the bone marrow microenvironment which contribute to the maintenance of the hematopoietic stem cell niche and exert immunoregulatory functions in innate and adaptive immunity. We analyze the immunobiology of MSCs derived from acute lymphoblastic leukemia (ALL) patients and their impact on NK cell function. In contrast to the inhibitory effects on the immune response exerted by MSCs from healthy donors (Healthy-MSCs), we demonstrate that MSCs derived from low/intermediate risk ALL patients at diagnosis (ALL-MSCs) promote an efficient NK cell response including cytokine production, phenotypic activation and most importantly, cytotoxicity. Longitudinal studies indicate that these immunostimulatory effects of ALL-MSCs are progressively attenuated. Healthy-MSCs adopt ALL-MSC-like immunomodulatory features when exposed to leukemia cells, acquiring the ability to stimulate NK cell antitumor function. The mechanisms underlying to these functional changes of ALL-MSCs include reduced production of soluble inhibitory factors, differential expression of costimulatory and coinhibitory molecules, increased expression of specific TLRs and Notch pathway activation. Collectively our findings indicate that, in response to leukemia cells, ALL-MSCs could mediate a host beneficial immunomodulatory effect by stimulating the antitumor innate immune response.
Department of Cell Biology, School of Medicine, Complutense University, 28040 Madrid, Spain.
Ana
A
Entrena
Department of Cell Biology, School of Medicine, Complutense University, 28040 Madrid, Spain.
Alberto
A
Varas
Department of Cell Biology, School of Medicine, Complutense University, 28040 Madrid, Spain.
Miriam
M
Vázquez
Department of Oncohematology, Hospital Niño Jesús, Madrid, Spain.
Gustavo J
GJ
Melen
Department of Cell Biology, School of Medicine, Complutense University, 28040 Madrid, Spain.
Lidia M
LM
Fernández-Sevilla
Cellular Biotechnology Unit, Institute for Health Carlos III, Majadahonda, Madrid, Spain.
Javier
J
García-Castro
Department of Oncohematology, Hospital Niño Jesús, Madrid, Spain.
Manuel
M
Ramírez
Department of Cell Biology, Faculty of Biology, Complutense University, Madrid, Spain.
Agustín G
AG
Zapata
Department of Cell Biology, School of Medicine, Complutense University, 28040 Madrid, Spain. Electronic address: avicente@ucm.es.
Ángeles
Á
Vicente
D000293:Adolescent; D001854:Bone Marrow Cells / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D064987:Cell- and Tissue-Based Therapy; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000473:pathology; D009367:Neoplasm Staging; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D012307:Risk Factors; D059016:Tumor Microenvironment / Q000276:immunology*
Acute lymphoblastic leukemia; Mesenchymal stem cells; NK cells; Tumor microenvironment