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S-15 in combination of Akt inhibitor promotes the expansion of CD45RA(−)CCR7(+) tumor infiltrating lymphocytes with high cytotoxic potential and downregulating PD-1(+)Tim-3(+) cells as well as regulatory T cells
BACKGROUND: Autologous tumor-infiltrating lymphocytes (Tils) immunotherapy is a promising treatment in patients with advanced hepatocellular cancer. Although Tils treatment has shown great promise, their persistence and the efficacy after adoptive-transfer are insufficient and remain a challenge. St...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889332/ https://www.ncbi.nlm.nih.gov/pubmed/31827396 http://dx.doi.org/10.1186/s12935-019-1043-3 |
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author | Xu, Benling Yuan, Long Chen, Guangyu Li, Tiepeng Zhou, Jinxue Zhang, Chengjuan Qin, Peng Muthana, Musleh M. Wang, Shengdian Du, Xuexiang Gao, Quanli |
author_facet | Xu, Benling Yuan, Long Chen, Guangyu Li, Tiepeng Zhou, Jinxue Zhang, Chengjuan Qin, Peng Muthana, Musleh M. Wang, Shengdian Du, Xuexiang Gao, Quanli |
author_sort | Xu, Benling |
collection | PubMed |
description | BACKGROUND: Autologous tumor-infiltrating lymphocytes (Tils) immunotherapy is a promising treatment in patients with advanced hepatocellular cancer. Although Tils treatment has shown great promise, their persistence and the efficacy after adoptive-transfer are insufficient and remain a challenge. Studies have demonstrated that IL-15 and Akt inhibitor can regulate T cell differentiation and memory. Here, we constructed S-15 (Super human IL-15), a fusion protein consisting of human IL-15, the sushi domain of the IL-15 receptor α chain and human IgG-Fc. Herein we compared the effects of S-15 with IL-2 or in combination with Akti on the expansion and activation of Tils. METHODS: Hepatocellular cancer tissues were obtained from 6 patients, Tils were expanded using IL-2, IL-2/S-15, IL-2/Akti or in combination IL-2/S-15/Akti. At day 10, anti-CD3 antibody was added to the culture media and expanded to day 25. The composition, exhaustion and T-cell differentiation markers (CD45RA/CCR7) were analyzed by flow cytometry. RESULTS: We found that IL-2/S-15/Akti expanded Tils and showed the highest percentage of central memory CD45RA(−)CCR7(+) phenotype prior to anti-CD3 antibody activation and after anti-CD3 antibody activation. T cells cultured with IL-2/S-15/Akti exhibited a mixture of CD4(+), CD8(+), and CD3(+)CD4(−)CD8(−) T cells; S-15 in combination with Akt inhibitor downregulated the expression of PD-1(+)Tim-3(+) on Tils and decreased the Tregs in Tils. Additionally, the Tils expanded in the presence of the Akt inhibitor and S-15 showed enhanced antitumor activity as indicated by the increase in IFN-γ producing tumor infiltrating CD8(+) T cells and without comprising the Tils expansion. CONCLUSION: Our study elucidates that IL-2/S-15/Akti expanded Tils and represent a viable source for the cellular therapy for patients with hepatocellular cancer. |
format | Online Article Text |
id | pubmed-6889332 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-68893322019-12-11 S-15 in combination of Akt inhibitor promotes the expansion of CD45RA(−)CCR7(+) tumor infiltrating lymphocytes with high cytotoxic potential and downregulating PD-1(+)Tim-3(+) cells as well as regulatory T cells Xu, Benling Yuan, Long Chen, Guangyu Li, Tiepeng Zhou, Jinxue Zhang, Chengjuan Qin, Peng Muthana, Musleh M. Wang, Shengdian Du, Xuexiang Gao, Quanli Cancer Cell Int Primary Research BACKGROUND: Autologous tumor-infiltrating lymphocytes (Tils) immunotherapy is a promising treatment in patients with advanced hepatocellular cancer. Although Tils treatment has shown great promise, their persistence and the efficacy after adoptive-transfer are insufficient and remain a challenge. Studies have demonstrated that IL-15 and Akt inhibitor can regulate T cell differentiation and memory. Here, we constructed S-15 (Super human IL-15), a fusion protein consisting of human IL-15, the sushi domain of the IL-15 receptor α chain and human IgG-Fc. Herein we compared the effects of S-15 with IL-2 or in combination with Akti on the expansion and activation of Tils. METHODS: Hepatocellular cancer tissues were obtained from 6 patients, Tils were expanded using IL-2, IL-2/S-15, IL-2/Akti or in combination IL-2/S-15/Akti. At day 10, anti-CD3 antibody was added to the culture media and expanded to day 25. The composition, exhaustion and T-cell differentiation markers (CD45RA/CCR7) were analyzed by flow cytometry. RESULTS: We found that IL-2/S-15/Akti expanded Tils and showed the highest percentage of central memory CD45RA(−)CCR7(+) phenotype prior to anti-CD3 antibody activation and after anti-CD3 antibody activation. T cells cultured with IL-2/S-15/Akti exhibited a mixture of CD4(+), CD8(+), and CD3(+)CD4(−)CD8(−) T cells; S-15 in combination with Akt inhibitor downregulated the expression of PD-1(+)Tim-3(+) on Tils and decreased the Tregs in Tils. Additionally, the Tils expanded in the presence of the Akt inhibitor and S-15 showed enhanced antitumor activity as indicated by the increase in IFN-γ producing tumor infiltrating CD8(+) T cells and without comprising the Tils expansion. CONCLUSION: Our study elucidates that IL-2/S-15/Akti expanded Tils and represent a viable source for the cellular therapy for patients with hepatocellular cancer. BioMed Central 2019-12-03 /pmc/articles/PMC6889332/ /pubmed/31827396 http://dx.doi.org/10.1186/s12935-019-1043-3 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Primary Research Xu, Benling Yuan, Long Chen, Guangyu Li, Tiepeng Zhou, Jinxue Zhang, Chengjuan Qin, Peng Muthana, Musleh M. Wang, Shengdian Du, Xuexiang Gao, Quanli S-15 in combination of Akt inhibitor promotes the expansion of CD45RA(−)CCR7(+) tumor infiltrating lymphocytes with high cytotoxic potential and downregulating PD-1(+)Tim-3(+) cells as well as regulatory T cells |
title | S-15 in combination of Akt inhibitor promotes the expansion of CD45RA(−)CCR7(+) tumor infiltrating lymphocytes with high cytotoxic potential and downregulating PD-1(+)Tim-3(+) cells as well as regulatory T cells |
title_full | S-15 in combination of Akt inhibitor promotes the expansion of CD45RA(−)CCR7(+) tumor infiltrating lymphocytes with high cytotoxic potential and downregulating PD-1(+)Tim-3(+) cells as well as regulatory T cells |
title_fullStr | S-15 in combination of Akt inhibitor promotes the expansion of CD45RA(−)CCR7(+) tumor infiltrating lymphocytes with high cytotoxic potential and downregulating PD-1(+)Tim-3(+) cells as well as regulatory T cells |
title_full_unstemmed | S-15 in combination of Akt inhibitor promotes the expansion of CD45RA(−)CCR7(+) tumor infiltrating lymphocytes with high cytotoxic potential and downregulating PD-1(+)Tim-3(+) cells as well as regulatory T cells |
title_short | S-15 in combination of Akt inhibitor promotes the expansion of CD45RA(−)CCR7(+) tumor infiltrating lymphocytes with high cytotoxic potential and downregulating PD-1(+)Tim-3(+) cells as well as regulatory T cells |
title_sort | s-15 in combination of akt inhibitor promotes the expansion of cd45ra(−)ccr7(+) tumor infiltrating lymphocytes with high cytotoxic potential and downregulating pd-1(+)tim-3(+) cells as well as regulatory t cells |
topic | Primary Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889332/ https://www.ncbi.nlm.nih.gov/pubmed/31827396 http://dx.doi.org/10.1186/s12935-019-1043-3 |
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