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Engineered Removal of PD-1 From the Surface of CD19 CAR-T Cells Results in Increased Activation and Diminished Survival

CAR-T cell therapy is the most advanced way to treat therapy resistant hematologic cancers, in particular B cell lymphomas and leukemias, with high efficiency. Donor T cells equipped ex vivo with chimeric receptor recognize target tumor cells and kill them using lytic granules. CAR-T cells that reco...

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Autores principales: Kalinin, R. S., Ukrainskaya, V. M., Chumakov, S. P., Moysenovich, A. M., Tereshchuk, V. M., Volkov, D. V., Pershin, D. S., Maksimov, E. G., Zhang, H., Maschan, M. A., Rubtsov, Y. P., Stepanov, A. V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548718/
https://www.ncbi.nlm.nih.gov/pubmed/34722633
http://dx.doi.org/10.3389/fmolb.2021.745286
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author Kalinin, R. S.
Ukrainskaya, V. M.
Chumakov, S. P.
Moysenovich, A. M.
Tereshchuk, V. M.
Volkov, D. V.
Pershin, D. S.
Maksimov, E. G.
Zhang, H.
Maschan, M. A.
Rubtsov, Y. P.
Stepanov, A. V.
author_facet Kalinin, R. S.
Ukrainskaya, V. M.
Chumakov, S. P.
Moysenovich, A. M.
Tereshchuk, V. M.
Volkov, D. V.
Pershin, D. S.
Maksimov, E. G.
Zhang, H.
Maschan, M. A.
Rubtsov, Y. P.
Stepanov, A. V.
author_sort Kalinin, R. S.
collection PubMed
description CAR-T cell therapy is the most advanced way to treat therapy resistant hematologic cancers, in particular B cell lymphomas and leukemias, with high efficiency. Donor T cells equipped ex vivo with chimeric receptor recognize target tumor cells and kill them using lytic granules. CAR-T cells that recognize CD19 marker of B cells (CD19 CAR-T) are considered the gold standard of CAR-T therapy and are approved by FDA. But in some cases, CD19 CAR-T cell therapy fails due to immune suppressive microenvironment. It is shown that tumor cells upregulate expression of PD-L1 surface molecule that binds and increases level and signal provided by PD-1 receptor on the surface of therapeutic CAR-T cells. Induction of this negative signaling results in functional impairment of cytotoxic program in CAR-T cells. Multiple attempts were made to block PD-1 signaling by reducing binding or surface level of PD-1 in CAR-T cells by various means. In this study we co-expressed CD19-CAR with PD-1-specific VHH domain of anti-PD-1 nanobody to block PD-1/PD-L1 signaling in CD19 CAR-T cells. Unexpectedly, despite increased activation of CAR-T cells with low level of PD-1, these T cells had reduced survival and diminished cytotoxicity. Functional impairment caused by disrupted PD-1 signaling was accompanied by faster maturation and upregulation of exhaustion marker TIGIT in CAR-T cells. We conclude that PD-1 in addition to its direct negative effect on CAR-induced signaling is required for attenuation of strong stimulation leading to cell death and functional exhaustion. These observations suggest that PD-1 downregulation should not be considered as the way to improve the quality of therapeutic CAR-T cells.
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spelling pubmed-85487182021-10-28 Engineered Removal of PD-1 From the Surface of CD19 CAR-T Cells Results in Increased Activation and Diminished Survival Kalinin, R. S. Ukrainskaya, V. M. Chumakov, S. P. Moysenovich, A. M. Tereshchuk, V. M. Volkov, D. V. Pershin, D. S. Maksimov, E. G. Zhang, H. Maschan, M. A. Rubtsov, Y. P. Stepanov, A. V. Front Mol Biosci Molecular Biosciences CAR-T cell therapy is the most advanced way to treat therapy resistant hematologic cancers, in particular B cell lymphomas and leukemias, with high efficiency. Donor T cells equipped ex vivo with chimeric receptor recognize target tumor cells and kill them using lytic granules. CAR-T cells that recognize CD19 marker of B cells (CD19 CAR-T) are considered the gold standard of CAR-T therapy and are approved by FDA. But in some cases, CD19 CAR-T cell therapy fails due to immune suppressive microenvironment. It is shown that tumor cells upregulate expression of PD-L1 surface molecule that binds and increases level and signal provided by PD-1 receptor on the surface of therapeutic CAR-T cells. Induction of this negative signaling results in functional impairment of cytotoxic program in CAR-T cells. Multiple attempts were made to block PD-1 signaling by reducing binding or surface level of PD-1 in CAR-T cells by various means. In this study we co-expressed CD19-CAR with PD-1-specific VHH domain of anti-PD-1 nanobody to block PD-1/PD-L1 signaling in CD19 CAR-T cells. Unexpectedly, despite increased activation of CAR-T cells with low level of PD-1, these T cells had reduced survival and diminished cytotoxicity. Functional impairment caused by disrupted PD-1 signaling was accompanied by faster maturation and upregulation of exhaustion marker TIGIT in CAR-T cells. We conclude that PD-1 in addition to its direct negative effect on CAR-induced signaling is required for attenuation of strong stimulation leading to cell death and functional exhaustion. These observations suggest that PD-1 downregulation should not be considered as the way to improve the quality of therapeutic CAR-T cells. Frontiers Media S.A. 2021-10-13 /pmc/articles/PMC8548718/ /pubmed/34722633 http://dx.doi.org/10.3389/fmolb.2021.745286 Text en Copyright © 2021 Kalinin, Ukrainskaya, Chumakov, Moysenovich, Tereshchuk, Volkov, Pershin, Maksimov, Zhang, Maschan, Rubtsov and Stepanov. 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 Molecular Biosciences
Kalinin, R. S.
Ukrainskaya, V. M.
Chumakov, S. P.
Moysenovich, A. M.
Tereshchuk, V. M.
Volkov, D. V.
Pershin, D. S.
Maksimov, E. G.
Zhang, H.
Maschan, M. A.
Rubtsov, Y. P.
Stepanov, A. V.
Engineered Removal of PD-1 From the Surface of CD19 CAR-T Cells Results in Increased Activation and Diminished Survival
title Engineered Removal of PD-1 From the Surface of CD19 CAR-T Cells Results in Increased Activation and Diminished Survival
title_full Engineered Removal of PD-1 From the Surface of CD19 CAR-T Cells Results in Increased Activation and Diminished Survival
title_fullStr Engineered Removal of PD-1 From the Surface of CD19 CAR-T Cells Results in Increased Activation and Diminished Survival
title_full_unstemmed Engineered Removal of PD-1 From the Surface of CD19 CAR-T Cells Results in Increased Activation and Diminished Survival
title_short Engineered Removal of PD-1 From the Surface of CD19 CAR-T Cells Results in Increased Activation and Diminished Survival
title_sort engineered removal of pd-1 from the surface of cd19 car-t cells results in increased activation and diminished survival
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548718/
https://www.ncbi.nlm.nih.gov/pubmed/34722633
http://dx.doi.org/10.3389/fmolb.2021.745286
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