Genetically re-engineered K562 cells significantly expand and functionally activate cord blood natural killer cells: Potential for adoptive cellular immunotherapy

Autor: William Quish, Mitchell S. Cairo, Carmella van de Ven, Jessica Hochberg, Janet Ayello, Allyson Flower, Laxmi V. Baxi, Yaya Chu
Rok vydání: 2017
Předmět:
Cytotoxicity
Immunologic
0301 basic medicine
Cancer Research
Cell Survival
Cell Culture Techniques
Cell Communication
Biology
Lymphocyte Activation
Immunotherapy
Adoptive
Peripheral blood mononuclear cell
Granzymes
Mice
03 medical and health sciences
0302 clinical medicine
Immune system
Lysosomal-Associated Membrane Protein 1
Cell Line
Tumor
hemic and lymphatic diseases
Genetics
Animals
Humans
Cell Engineering
Molecular Biology
Mice
Knockout
Lymphokine-activated killer cell
Perforin
Cell Biology
Hematology
Fetal Blood
Xenograft Model Antitumor Assays
Killer Cells
Natural
Granzyme B
Transplantation
030104 developmental biology
030220 oncology & carcinogenesis
Cord blood
Immunology
Leukocytes
Mononuclear
biology.protein
Heterografts
Receptors
Natural Killer Cell
Stem cell
Genetic Engineering
K562 Cells
Biomarkers
Zdroj: Experimental Hematology. 46:38-47
ISSN: 0301-472X
DOI: 10.1016/j.exphem.2016.10.003
Popis: Natural killer (NK) cells play a significant role in reducing relapse in patients with hematological malignancies after allogeneic stem cell transplantation, but NK cell number and naturally occurring inhibitory signals limit their capability. Interleukin-15 (IL-15) and 4-1BBL are important modulators of NK expansion and functional activation. To overcome these limitations, cord blood mononuclear cells (CB MNCs) were ex vivo expanded for 7 days with genetically modified K562-mbIL15-41BBL (MODK562) or wild-type K562 (WTK562). NK cell expansion; expression of lysosome-associated membrane protein-1 (LAMP-1), granzyme B, and perforin; and in vitro and in vivo cytotoxicity against B-cell non-Hodgkin lymphoma (B-NHL) were evaluated. In vivo tumor growth in B-NHL-xenografted nonobese diabetic severe combined immune deficient (NOD-scid) gamma (NSG) mice was monitored by tumor volume, cell number, and survival. CB MNCs cultured with MODK562 compared with WTK562 demonstrated significantly increased NK expansion (thirty-fivefold, p 0.05); LAMP-1 (p 0.05), granzyme B, and perforin expression (p 0.001); and in vitro cytotoxicity against B-NHL (p 0.01). Xenografted mice treated with MODK562 CB experienced significantly decreased B-NHL tumor volume (p = 0.0086) and B-NHL cell numbers (p 0.01) at 5 weeks and significantly increased survival (p 0.001) at 10 weeks compared with WTK562. In summary, MODK562 significantly enhanced CB NK expansion and cytotoxicity, enhanced survival in a human Burkitt's lymphoma xenograft NSG model, and could be used in the future as adoptive cellular immunotherapy after umbilical CB transplantation. Future directions include expanding anti-CD20 chimeric receptor-modified CB NK cells to enhance B-NHL targeting in vitro and in vivo.
Databáze: OpenAIRE
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