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Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft
Existing patient-derived xenograft (PDX) mouse models of solid tumors lack a fully tumor donor–matched, syngeneic, and functional immune system. We developed a model that overcomes these limitations by engrafting lymphopenic recipient mice with a fresh, undisrupted piece of solid tumor, whereby tumo...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410059/ https://www.ncbi.nlm.nih.gov/pubmed/34081628 http://dx.doi.org/10.1172/jci.insight.140116 |
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author | Le, Duy Tri Huynh, Tridu R. Burt, Bryan Van Buren, George Abeynaike, Shawn A. Zalfa, Cristina Nikzad, Rana Kheradmand, Farrah Tyner, John J. Paust, Silke |
author_facet | Le, Duy Tri Huynh, Tridu R. Burt, Bryan Van Buren, George Abeynaike, Shawn A. Zalfa, Cristina Nikzad, Rana Kheradmand, Farrah Tyner, John J. Paust, Silke |
author_sort | Le, Duy Tri |
collection | PubMed |
description | Existing patient-derived xenograft (PDX) mouse models of solid tumors lack a fully tumor donor–matched, syngeneic, and functional immune system. We developed a model that overcomes these limitations by engrafting lymphopenic recipient mice with a fresh, undisrupted piece of solid tumor, whereby tumor-infiltrating lymphocytes (TILs) persisted in the recipient mice for several weeks. Successful tumor engraftment was achieved in 83% to 89% of TIL-PDX mice, and these were seen to harbor exhausted immuno-effector as well as functional immunoregulatory cells persisting for at least 6 months postengraftment. Combined treatment with interleukin-15 stimulation and immune checkpoint inhibition resulted in complete or partial tumor response in this model. Further, depletion of cytotoxic T lymphocytes and/or natural killer cells before combined immunotherapy revealed that both cell types were required for maximal tumor regression. Our TIL-PDX model provides a valuable resource for powerful mechanistic and therapeutic studies in solid tumors. |
format | Online Article Text |
id | pubmed-8410059 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-84100592021-09-07 Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft Le, Duy Tri Huynh, Tridu R. Burt, Bryan Van Buren, George Abeynaike, Shawn A. Zalfa, Cristina Nikzad, Rana Kheradmand, Farrah Tyner, John J. Paust, Silke JCI Insight Resource and Technical Advance Existing patient-derived xenograft (PDX) mouse models of solid tumors lack a fully tumor donor–matched, syngeneic, and functional immune system. We developed a model that overcomes these limitations by engrafting lymphopenic recipient mice with a fresh, undisrupted piece of solid tumor, whereby tumor-infiltrating lymphocytes (TILs) persisted in the recipient mice for several weeks. Successful tumor engraftment was achieved in 83% to 89% of TIL-PDX mice, and these were seen to harbor exhausted immuno-effector as well as functional immunoregulatory cells persisting for at least 6 months postengraftment. Combined treatment with interleukin-15 stimulation and immune checkpoint inhibition resulted in complete or partial tumor response in this model. Further, depletion of cytotoxic T lymphocytes and/or natural killer cells before combined immunotherapy revealed that both cell types were required for maximal tumor regression. Our TIL-PDX model provides a valuable resource for powerful mechanistic and therapeutic studies in solid tumors. American Society for Clinical Investigation 2021-07-08 /pmc/articles/PMC8410059/ /pubmed/34081628 http://dx.doi.org/10.1172/jci.insight.140116 Text en © 2021 Le et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Resource and Technical Advance Le, Duy Tri Huynh, Tridu R. Burt, Bryan Van Buren, George Abeynaike, Shawn A. Zalfa, Cristina Nikzad, Rana Kheradmand, Farrah Tyner, John J. Paust, Silke Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft |
title | Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft |
title_full | Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft |
title_fullStr | Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft |
title_full_unstemmed | Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft |
title_short | Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft |
title_sort | natural killer cells and cytotoxic t lymphocytes are required to clear solid tumor in a patient-derived xenograft |
topic | Resource and Technical Advance |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410059/ https://www.ncbi.nlm.nih.gov/pubmed/34081628 http://dx.doi.org/10.1172/jci.insight.140116 |
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