Cargando…
Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells
Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as chemotherapy and radiotherapy, thereby repopulating...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356940/ https://www.ncbi.nlm.nih.gov/pubmed/30646520 http://dx.doi.org/10.3390/cancers11010085 |
_version_ | 1783391674755448832 |
---|---|
author | Luna, Jesus I. Grossenbacher, Steven K. Sturgill, Ian R. Ames, Erik Judge, Sean J. Bouzid, Lyes A. Darrow, Morgan A. Murphy, William J. Canter, Robert J. |
author_facet | Luna, Jesus I. Grossenbacher, Steven K. Sturgill, Ian R. Ames, Erik Judge, Sean J. Bouzid, Lyes A. Darrow, Morgan A. Murphy, William J. Canter, Robert J. |
author_sort | Luna, Jesus I. |
collection | PubMed |
description | Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as chemotherapy and radiotherapy, thereby repopulating the tumor and seeding relapse and/or metastasis. We have previously shown that natural killer (NK) cells preferentially target stem-like tumor cells via non- major histocompatibility complex (MHC) restricted mechanisms. Here, we demonstrated that the proteasome inhibitor, bortezomib, augments NK cell targeting of stem cell-like tumor cells against multiple solid human tumor-derived cancer lines and primary tissue samples. Mechanistically, this was mediated by the upregulation of cell surface NK ligands MHC class I chain-related protein A and B (MICA and MICB) on aldehyde dehydrogenases (ALDH)-positive CSCs. The increased expression of MICA and MICB on CSC targets thereby enhanced NK cell mediated killing in vitro and ex vivo from both human primary tumor and patient-derived xenograft samples. In vivo, the combination of bortezomib and allogeneic NK cell adoptive transfer in immunodeficient mice led to increased elimination of CSCs as well as tumor growth delay of orthotopic glioblastoma tumors. Taken together, our data support the combination bortezomib and NK transfer as a strategy for both CSC targeting and potentially improved outcomes in clinical cancer patients. |
format | Online Article Text |
id | pubmed-6356940 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-63569402019-02-05 Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells Luna, Jesus I. Grossenbacher, Steven K. Sturgill, Ian R. Ames, Erik Judge, Sean J. Bouzid, Lyes A. Darrow, Morgan A. Murphy, William J. Canter, Robert J. Cancers (Basel) Article Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as chemotherapy and radiotherapy, thereby repopulating the tumor and seeding relapse and/or metastasis. We have previously shown that natural killer (NK) cells preferentially target stem-like tumor cells via non- major histocompatibility complex (MHC) restricted mechanisms. Here, we demonstrated that the proteasome inhibitor, bortezomib, augments NK cell targeting of stem cell-like tumor cells against multiple solid human tumor-derived cancer lines and primary tissue samples. Mechanistically, this was mediated by the upregulation of cell surface NK ligands MHC class I chain-related protein A and B (MICA and MICB) on aldehyde dehydrogenases (ALDH)-positive CSCs. The increased expression of MICA and MICB on CSC targets thereby enhanced NK cell mediated killing in vitro and ex vivo from both human primary tumor and patient-derived xenograft samples. In vivo, the combination of bortezomib and allogeneic NK cell adoptive transfer in immunodeficient mice led to increased elimination of CSCs as well as tumor growth delay of orthotopic glioblastoma tumors. Taken together, our data support the combination bortezomib and NK transfer as a strategy for both CSC targeting and potentially improved outcomes in clinical cancer patients. MDPI 2019-01-14 /pmc/articles/PMC6356940/ /pubmed/30646520 http://dx.doi.org/10.3390/cancers11010085 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Luna, Jesus I. Grossenbacher, Steven K. Sturgill, Ian R. Ames, Erik Judge, Sean J. Bouzid, Lyes A. Darrow, Morgan A. Murphy, William J. Canter, Robert J. Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells |
title | Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells |
title_full | Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells |
title_fullStr | Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells |
title_full_unstemmed | Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells |
title_short | Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells |
title_sort | bortezomib augments natural killer cell targeting of stem-like tumor cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356940/ https://www.ncbi.nlm.nih.gov/pubmed/30646520 http://dx.doi.org/10.3390/cancers11010085 |
work_keys_str_mv | AT lunajesusi bortezomibaugmentsnaturalkillercelltargetingofstemliketumorcells AT grossenbacherstevenk bortezomibaugmentsnaturalkillercelltargetingofstemliketumorcells AT sturgillianr bortezomibaugmentsnaturalkillercelltargetingofstemliketumorcells AT ameserik bortezomibaugmentsnaturalkillercelltargetingofstemliketumorcells AT judgeseanj bortezomibaugmentsnaturalkillercelltargetingofstemliketumorcells AT bouzidlyesa bortezomibaugmentsnaturalkillercelltargetingofstemliketumorcells AT darrowmorgana bortezomibaugmentsnaturalkillercelltargetingofstemliketumorcells AT murphywilliamj bortezomibaugmentsnaturalkillercelltargetingofstemliketumorcells AT canterrobertj bortezomibaugmentsnaturalkillercelltargetingofstemliketumorcells |