Cargando…
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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1783293291503026176 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5771627 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT otegbeyefolashade inhibitingtgfbetasignalingpreservesthefunctionofhighlyactivatedinvitroexpandednaturalkillercellsinamlandcoloncancermodels AT ojoevelyn inhibitingtgfbetasignalingpreservesthefunctionofhighlyactivatedinvitroexpandednaturalkillercellsinamlandcoloncancermodels AT moretonstephen inhibitingtgfbetasignalingpreservesthefunctionofhighlyactivatedinvitroexpandednaturalkillercellsinamlandcoloncancermodels AT mackowskinathan inhibitingtgfbetasignalingpreservesthefunctionofhighlyactivatedinvitroexpandednaturalkillercellsinamlandcoloncancermodels AT leedeana inhibitingtgfbetasignalingpreservesthefunctionofhighlyactivatedinvitroexpandednaturalkillercellsinamlandcoloncancermodels AT delimamarcos inhibitingtgfbetasignalingpreservesthefunctionofhighlyactivatedinvitroexpandednaturalkillercellsinamlandcoloncancermodels AT walddavidn inhibitingtgfbetasignalingpreservesthefunctionofhighlyactivatedinvitroexpandednaturalkillercellsinamlandcoloncancermodels |