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Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models

Natural killer cells harnessed from healthy individuals can be expanded ex vivo using various platforms to produce large doses for adoptive transfer into cancer patients. During such expansion, NK cells are increasingly activated and more efficient at killing cancer cells. Adoptive transfer however...

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Autores principales: Otegbeye, Folashade, Ojo, Evelyn, Moreton, Stephen, Mackowski, Nathan, Lee, Dean A., de Lima, Marcos, Wald, David N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771627/
https://www.ncbi.nlm.nih.gov/pubmed/29342200
http://dx.doi.org/10.1371/journal.pone.0191358
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author Otegbeye, Folashade
Ojo, Evelyn
Moreton, Stephen
Mackowski, Nathan
Lee, Dean A.
de Lima, Marcos
Wald, David N.
author_facet Otegbeye, Folashade
Ojo, Evelyn
Moreton, Stephen
Mackowski, Nathan
Lee, Dean A.
de Lima, Marcos
Wald, David N.
author_sort Otegbeye, Folashade
collection PubMed
description Natural killer cells harnessed from healthy individuals can be expanded ex vivo using various platforms to produce large doses for adoptive transfer into cancer patients. During such expansion, NK cells are increasingly activated and more efficient at killing cancer cells. Adoptive transfer however introduces these activated cells into a highly immunosuppressive tumor microenvironment mediated in part by excessive transforming growth factor beta (TGF-beta) from both cancer cells and their surrounding stroma. This microenvironment ultimately limits the clinical efficacy of NK cell therapy. In this study, we examined the use of a TGF-beta receptor kinase inhibitor, LY2157299, in preserving the cytotoxic function of ex vivo expanded, highly activated NK cells following sustained exposure to pathologic levels of TGF-beta in vitro and in a liver metastases model of colon cancer. Using myeloid leukemia and colon cancer cell lines, we show that the TGF-beta driven impairment of NK cell cytotoxicity is mitigated by LY2157299. We demonstrate this effect using quantitative cytotoxicity assays as well as by showing a preserved activated phenotype with high NKG2D/CD16 expression and enhanced cytokine production. In a mouse liver metastases model of colon cancer, we observed significantly improved eradication of liver metastases in mice treated with adoptive NK cells combined with LY2157299 compared with mice receiving NK cells or TGF beta inhibition alone. We propose that the therapeutic efficacy of adoptive NK cell therapy clinically will be markedly enhanced by complementary approaches targeting TGF-beta signaling in vivo.
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spelling pubmed-57716272018-01-23 Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models Otegbeye, Folashade Ojo, Evelyn Moreton, Stephen Mackowski, Nathan Lee, Dean A. de Lima, Marcos Wald, David N. PLoS One Research Article Natural killer cells harnessed from healthy individuals can be expanded ex vivo using various platforms to produce large doses for adoptive transfer into cancer patients. During such expansion, NK cells are increasingly activated and more efficient at killing cancer cells. Adoptive transfer however introduces these activated cells into a highly immunosuppressive tumor microenvironment mediated in part by excessive transforming growth factor beta (TGF-beta) from both cancer cells and their surrounding stroma. This microenvironment ultimately limits the clinical efficacy of NK cell therapy. In this study, we examined the use of a TGF-beta receptor kinase inhibitor, LY2157299, in preserving the cytotoxic function of ex vivo expanded, highly activated NK cells following sustained exposure to pathologic levels of TGF-beta in vitro and in a liver metastases model of colon cancer. Using myeloid leukemia and colon cancer cell lines, we show that the TGF-beta driven impairment of NK cell cytotoxicity is mitigated by LY2157299. We demonstrate this effect using quantitative cytotoxicity assays as well as by showing a preserved activated phenotype with high NKG2D/CD16 expression and enhanced cytokine production. In a mouse liver metastases model of colon cancer, we observed significantly improved eradication of liver metastases in mice treated with adoptive NK cells combined with LY2157299 compared with mice receiving NK cells or TGF beta inhibition alone. We propose that the therapeutic efficacy of adoptive NK cell therapy clinically will be markedly enhanced by complementary approaches targeting TGF-beta signaling in vivo. Public Library of Science 2018-01-17 /pmc/articles/PMC5771627/ /pubmed/29342200 http://dx.doi.org/10.1371/journal.pone.0191358 Text en © 2018 Otegbeye et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Otegbeye, Folashade
Ojo, Evelyn
Moreton, Stephen
Mackowski, Nathan
Lee, Dean A.
de Lima, Marcos
Wald, David N.
Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models
title Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models
title_full Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models
title_fullStr Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models
title_full_unstemmed Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models
title_short Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models
title_sort inhibiting tgf-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in aml and colon cancer models
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771627/
https://www.ncbi.nlm.nih.gov/pubmed/29342200
http://dx.doi.org/10.1371/journal.pone.0191358
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