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Chimeric CTLA4-CD28-CD3z T Cells Potentiate Antitumor Activity Against CD80/CD86–Positive B Cell Malignancies

The adoptive transfer of chimeric antigen receptor T (CAR T) cells have been recognized as a promising therapeutic strategy for the treatment of hematological malignancies; however, clinical success using CAR T cells for the treatment of solid tumors are still limited since the T-cell function is in...

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Autores principales: Lin, Shouheng, Cheng, Lin, Ye, Wei, Li, Shanglin, Zheng, Diwei, Qin, Le, Wu, Qiting, Long, Youguo, Lin, Simiao, Wang, Suna, Huang, Guohua, Li, Peng, Yao, Yao, Sun, Xiaofang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050336/
https://www.ncbi.nlm.nih.gov/pubmed/33868277
http://dx.doi.org/10.3389/fimmu.2021.642528
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author Lin, Shouheng
Cheng, Lin
Ye, Wei
Li, Shanglin
Zheng, Diwei
Qin, Le
Wu, Qiting
Long, Youguo
Lin, Simiao
Wang, Suna
Huang, Guohua
Li, Peng
Yao, Yao
Sun, Xiaofang
author_facet Lin, Shouheng
Cheng, Lin
Ye, Wei
Li, Shanglin
Zheng, Diwei
Qin, Le
Wu, Qiting
Long, Youguo
Lin, Simiao
Wang, Suna
Huang, Guohua
Li, Peng
Yao, Yao
Sun, Xiaofang
author_sort Lin, Shouheng
collection PubMed
description The adoptive transfer of chimeric antigen receptor T (CAR T) cells have been recognized as a promising therapeutic strategy for the treatment of hematological malignancies; however, clinical success using CAR T cells for the treatment of solid tumors are still limited since the T-cell function is inhibited by negative signals in the microenvironment of solid tumors. CTLA4 is a well-known immune checkpoint molecule, thus we developed a novel CAR by converting this negative signal to positive signal. The CAR developed consists of the extracellular and transmembrane domains of CTLA4 and the cytoplasmic domains of CD28 and CD3z (CTLA4-CAR T). CTLA4-CAR T cells exhibited superior cytokine secreting activities and cytotoxic to tumor cells in vitro and in xenograft models. CTLA4-CAR T cells were found to accumulate in tumors and are toxic to myeloid-derived suppressor cells (MDSCs) without signs of severe GVHD and CRS in preclinical models. Thus, this chimeric CTLA4-CAR can enhance the antitumor activity of CAR T cells and shed light on the strategy of using armed CAR T cells to target the immunomodulatory tumor microenvironment.
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spelling pubmed-80503362021-04-17 Chimeric CTLA4-CD28-CD3z T Cells Potentiate Antitumor Activity Against CD80/CD86–Positive B Cell Malignancies Lin, Shouheng Cheng, Lin Ye, Wei Li, Shanglin Zheng, Diwei Qin, Le Wu, Qiting Long, Youguo Lin, Simiao Wang, Suna Huang, Guohua Li, Peng Yao, Yao Sun, Xiaofang Front Immunol Immunology The adoptive transfer of chimeric antigen receptor T (CAR T) cells have been recognized as a promising therapeutic strategy for the treatment of hematological malignancies; however, clinical success using CAR T cells for the treatment of solid tumors are still limited since the T-cell function is inhibited by negative signals in the microenvironment of solid tumors. CTLA4 is a well-known immune checkpoint molecule, thus we developed a novel CAR by converting this negative signal to positive signal. The CAR developed consists of the extracellular and transmembrane domains of CTLA4 and the cytoplasmic domains of CD28 and CD3z (CTLA4-CAR T). CTLA4-CAR T cells exhibited superior cytokine secreting activities and cytotoxic to tumor cells in vitro and in xenograft models. CTLA4-CAR T cells were found to accumulate in tumors and are toxic to myeloid-derived suppressor cells (MDSCs) without signs of severe GVHD and CRS in preclinical models. Thus, this chimeric CTLA4-CAR can enhance the antitumor activity of CAR T cells and shed light on the strategy of using armed CAR T cells to target the immunomodulatory tumor microenvironment. Frontiers Media S.A. 2021-04-02 /pmc/articles/PMC8050336/ /pubmed/33868277 http://dx.doi.org/10.3389/fimmu.2021.642528 Text en Copyright © 2021 Lin, Cheng, Ye, Li, Zheng, Qin, Wu, Long, Lin, Wang, Huang, Li, Yao and Sun https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Lin, Shouheng
Cheng, Lin
Ye, Wei
Li, Shanglin
Zheng, Diwei
Qin, Le
Wu, Qiting
Long, Youguo
Lin, Simiao
Wang, Suna
Huang, Guohua
Li, Peng
Yao, Yao
Sun, Xiaofang
Chimeric CTLA4-CD28-CD3z T Cells Potentiate Antitumor Activity Against CD80/CD86–Positive B Cell Malignancies
title Chimeric CTLA4-CD28-CD3z T Cells Potentiate Antitumor Activity Against CD80/CD86–Positive B Cell Malignancies
title_full Chimeric CTLA4-CD28-CD3z T Cells Potentiate Antitumor Activity Against CD80/CD86–Positive B Cell Malignancies
title_fullStr Chimeric CTLA4-CD28-CD3z T Cells Potentiate Antitumor Activity Against CD80/CD86–Positive B Cell Malignancies
title_full_unstemmed Chimeric CTLA4-CD28-CD3z T Cells Potentiate Antitumor Activity Against CD80/CD86–Positive B Cell Malignancies
title_short Chimeric CTLA4-CD28-CD3z T Cells Potentiate Antitumor Activity Against CD80/CD86–Positive B Cell Malignancies
title_sort chimeric ctla4-cd28-cd3z t cells potentiate antitumor activity against cd80/cd86–positive b cell malignancies
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050336/
https://www.ncbi.nlm.nih.gov/pubmed/33868277
http://dx.doi.org/10.3389/fimmu.2021.642528
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