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Anti‐PD‐L1/TGF‐βR fusion protein (SHR‐1701) overcomes disrupted lymphocyte recovery‐induced resistance to PD‐1/PD‐L1 inhibitors in lung cancer

BACKGROUND: Second‐generation programmed cell death‐protein 1/programmed death‐ligand 1 (PD‐1/PD‐L1) inhibitors, such as bintrafusp alfa (M7824), SHR‐1701, and YM101, have been developed to simultaneously block PD‐1/PD‐L1 and transforming growth factor‐beta/transforming growth factor‐beta receptor (...

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Autores principales: Cheng, Bo, Ding, Kaikai, Chen, Pengxiang, Ji, Jianxiong, Luo, Tao, Guo, Xiaofan, Qiu, Wei, Ma, Chunhong, Meng, Xue, Wang, Jian, Yu, Jinming, Liu, Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8753312/
https://www.ncbi.nlm.nih.gov/pubmed/34981670
http://dx.doi.org/10.1002/cac2.12244
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author Cheng, Bo
Ding, Kaikai
Chen, Pengxiang
Ji, Jianxiong
Luo, Tao
Guo, Xiaofan
Qiu, Wei
Ma, Chunhong
Meng, Xue
Wang, Jian
Yu, Jinming
Liu, Yuan
author_facet Cheng, Bo
Ding, Kaikai
Chen, Pengxiang
Ji, Jianxiong
Luo, Tao
Guo, Xiaofan
Qiu, Wei
Ma, Chunhong
Meng, Xue
Wang, Jian
Yu, Jinming
Liu, Yuan
author_sort Cheng, Bo
collection PubMed
description BACKGROUND: Second‐generation programmed cell death‐protein 1/programmed death‐ligand 1 (PD‐1/PD‐L1) inhibitors, such as bintrafusp alfa (M7824), SHR‐1701, and YM101, have been developed to simultaneously block PD‐1/PD‐L1 and transforming growth factor‐beta/transforming growth factor‐beta receptor (TGF‐β/TGF‐βR). Consequently, it is necessary to identify predictive factors of lung cancer patients who are not only resistant to PD‐1/PD‐L1 inhibitors but also sensitive to bifunctional drugs. The purpose of this study was to search for such predictors. METHODS: Multivariable Cox regression was used to study the association between the clinical outcome of treatment with PD‐1/PD‐L1 inhibitors and lymphocyte recovery after lymphopenia in lung cancer patients. Murine CMT167 lung cancer cells were engineered to express the firefly luciferase gene and implanted orthotopically in the lung of syngeneic mice. Bioluminescence imaging, flow cytometry, and immunohistochemistry were employed to determine response to immunotherapy and function of tumor‐infiltrating immune cells. RESULTS: For lung cancer patients treated with anti‐PD‐1/PD‐L1 antibodies, poor lymphocyte recovery was associated with a shorter progression‐free survival (PFS; P < 0.001), an accumulation of regulatory T cells (Tregs), and an elimination of CD8(+) T cells in the peripheral blood. Levels of CD8(+) T cells and Treg cells were also imbalanced in the tumors and peripheral immune organs of mice with poor lymphocyte recovery after chemotherapy. Moreover, these mice failed to respond to anti‐PD‐1 antibodies but remained sensitive to the anti‐PD‐L1/TGF‐βR fusion protein (SHR‐1701). Consistently, SHR‐1701 but not anti‐PD‐1 antibodies, markedly enhanced IFN‐γ production and Ki‐67 expression in peripheral CD8(+) T cells from patients with impaired lymphocyte recovery. CONCLUSIONS: Lung cancer patients with poor lymphocyte recovery and suffering from persistent lymphopenia after previous chemotherapy are resistant to anti‐PD‐1/PD‐L1 antibodies but might be sensitive to second‐generation agents such as SHR‐1701.
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spelling pubmed-87533122022-01-14 Anti‐PD‐L1/TGF‐βR fusion protein (SHR‐1701) overcomes disrupted lymphocyte recovery‐induced resistance to PD‐1/PD‐L1 inhibitors in lung cancer Cheng, Bo Ding, Kaikai Chen, Pengxiang Ji, Jianxiong Luo, Tao Guo, Xiaofan Qiu, Wei Ma, Chunhong Meng, Xue Wang, Jian Yu, Jinming Liu, Yuan Cancer Commun (Lond) Original Articles BACKGROUND: Second‐generation programmed cell death‐protein 1/programmed death‐ligand 1 (PD‐1/PD‐L1) inhibitors, such as bintrafusp alfa (M7824), SHR‐1701, and YM101, have been developed to simultaneously block PD‐1/PD‐L1 and transforming growth factor‐beta/transforming growth factor‐beta receptor (TGF‐β/TGF‐βR). Consequently, it is necessary to identify predictive factors of lung cancer patients who are not only resistant to PD‐1/PD‐L1 inhibitors but also sensitive to bifunctional drugs. The purpose of this study was to search for such predictors. METHODS: Multivariable Cox regression was used to study the association between the clinical outcome of treatment with PD‐1/PD‐L1 inhibitors and lymphocyte recovery after lymphopenia in lung cancer patients. Murine CMT167 lung cancer cells were engineered to express the firefly luciferase gene and implanted orthotopically in the lung of syngeneic mice. Bioluminescence imaging, flow cytometry, and immunohistochemistry were employed to determine response to immunotherapy and function of tumor‐infiltrating immune cells. RESULTS: For lung cancer patients treated with anti‐PD‐1/PD‐L1 antibodies, poor lymphocyte recovery was associated with a shorter progression‐free survival (PFS; P < 0.001), an accumulation of regulatory T cells (Tregs), and an elimination of CD8(+) T cells in the peripheral blood. Levels of CD8(+) T cells and Treg cells were also imbalanced in the tumors and peripheral immune organs of mice with poor lymphocyte recovery after chemotherapy. Moreover, these mice failed to respond to anti‐PD‐1 antibodies but remained sensitive to the anti‐PD‐L1/TGF‐βR fusion protein (SHR‐1701). Consistently, SHR‐1701 but not anti‐PD‐1 antibodies, markedly enhanced IFN‐γ production and Ki‐67 expression in peripheral CD8(+) T cells from patients with impaired lymphocyte recovery. CONCLUSIONS: Lung cancer patients with poor lymphocyte recovery and suffering from persistent lymphopenia after previous chemotherapy are resistant to anti‐PD‐1/PD‐L1 antibodies but might be sensitive to second‐generation agents such as SHR‐1701. John Wiley and Sons Inc. 2022-01-03 /pmc/articles/PMC8753312/ /pubmed/34981670 http://dx.doi.org/10.1002/cac2.12244 Text en © 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Cheng, Bo
Ding, Kaikai
Chen, Pengxiang
Ji, Jianxiong
Luo, Tao
Guo, Xiaofan
Qiu, Wei
Ma, Chunhong
Meng, Xue
Wang, Jian
Yu, Jinming
Liu, Yuan
Anti‐PD‐L1/TGF‐βR fusion protein (SHR‐1701) overcomes disrupted lymphocyte recovery‐induced resistance to PD‐1/PD‐L1 inhibitors in lung cancer
title Anti‐PD‐L1/TGF‐βR fusion protein (SHR‐1701) overcomes disrupted lymphocyte recovery‐induced resistance to PD‐1/PD‐L1 inhibitors in lung cancer
title_full Anti‐PD‐L1/TGF‐βR fusion protein (SHR‐1701) overcomes disrupted lymphocyte recovery‐induced resistance to PD‐1/PD‐L1 inhibitors in lung cancer
title_fullStr Anti‐PD‐L1/TGF‐βR fusion protein (SHR‐1701) overcomes disrupted lymphocyte recovery‐induced resistance to PD‐1/PD‐L1 inhibitors in lung cancer
title_full_unstemmed Anti‐PD‐L1/TGF‐βR fusion protein (SHR‐1701) overcomes disrupted lymphocyte recovery‐induced resistance to PD‐1/PD‐L1 inhibitors in lung cancer
title_short Anti‐PD‐L1/TGF‐βR fusion protein (SHR‐1701) overcomes disrupted lymphocyte recovery‐induced resistance to PD‐1/PD‐L1 inhibitors in lung cancer
title_sort anti‐pd‐l1/tgf‐βr fusion protein (shr‐1701) overcomes disrupted lymphocyte recovery‐induced resistance to pd‐1/pd‐l1 inhibitors in lung cancer
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8753312/
https://www.ncbi.nlm.nih.gov/pubmed/34981670
http://dx.doi.org/10.1002/cac2.12244
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