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Elimination of acquired resistance to PD-1 blockade via the concurrent depletion of tumour cells and immunosuppressive cells

Antigen release resulting from the death of tumour cells induced by chemotherapies and targeted therapies can augment the antitumor responses induced by immune checkpoint blockade (ICB). However, tumours responding to ICB therapies often become resistant to them. Here, we show that the specific targ...

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Autores principales: Xue, Gang, Wang, Ziyu, Zheng, Ningbo, Fang, Jing, Mao, Chengqiong, Li, Xiaoyin, Jin, Guangxu, Ming, Xin, Lu, Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595849/
https://www.ncbi.nlm.nih.gov/pubmed/34725506
http://dx.doi.org/10.1038/s41551-021-00799-6
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author Xue, Gang
Wang, Ziyu
Zheng, Ningbo
Fang, Jing
Mao, Chengqiong
Li, Xiaoyin
Jin, Guangxu
Ming, Xin
Lu, Yong
author_facet Xue, Gang
Wang, Ziyu
Zheng, Ningbo
Fang, Jing
Mao, Chengqiong
Li, Xiaoyin
Jin, Guangxu
Ming, Xin
Lu, Yong
author_sort Xue, Gang
collection PubMed
description Antigen release resulting from the death of tumour cells induced by chemotherapies and targeted therapies can augment the antitumor responses induced by immune checkpoint blockade (ICB). However, tumours responding to ICB therapies often become resistant to them. Here, we show that the specific targeting of tumour cells promotes the growth of tumour-cell variants that are resistant to ICB, and that the acquired resistance can be overcome via the concurrent depletion of tumour cells and of major types of immunosuppressive cells via a monoclonal antibody binding the enzyme CD73 (which we identified is highly expressed on tumour cells and on regulatory T cells, myeloid-derived suppressor cells and tumour-associated macrophages, yet not on cytolytic T lymphocytes, natural killer cells and dendritic cells). In mice with murine tumours, the systemic administration of anti-PD1 antibodies and anti-CD73 antibodies conjugated to a near-infrared dye subverted near-infrared-irradiated tumours from acquiring resistance to ICB and resulted in the eradication of advanced tumours. The elimination of immunosuppressive cells may overcome acquired resistance to ICB across a range of tumour types and combination therapies.
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spelling pubmed-85958492022-05-01 Elimination of acquired resistance to PD-1 blockade via the concurrent depletion of tumour cells and immunosuppressive cells Xue, Gang Wang, Ziyu Zheng, Ningbo Fang, Jing Mao, Chengqiong Li, Xiaoyin Jin, Guangxu Ming, Xin Lu, Yong Nat Biomed Eng Article Antigen release resulting from the death of tumour cells induced by chemotherapies and targeted therapies can augment the antitumor responses induced by immune checkpoint blockade (ICB). However, tumours responding to ICB therapies often become resistant to them. Here, we show that the specific targeting of tumour cells promotes the growth of tumour-cell variants that are resistant to ICB, and that the acquired resistance can be overcome via the concurrent depletion of tumour cells and of major types of immunosuppressive cells via a monoclonal antibody binding the enzyme CD73 (which we identified is highly expressed on tumour cells and on regulatory T cells, myeloid-derived suppressor cells and tumour-associated macrophages, yet not on cytolytic T lymphocytes, natural killer cells and dendritic cells). In mice with murine tumours, the systemic administration of anti-PD1 antibodies and anti-CD73 antibodies conjugated to a near-infrared dye subverted near-infrared-irradiated tumours from acquiring resistance to ICB and resulted in the eradication of advanced tumours. The elimination of immunosuppressive cells may overcome acquired resistance to ICB across a range of tumour types and combination therapies. 2021-11-01 2021-11 /pmc/articles/PMC8595849/ /pubmed/34725506 http://dx.doi.org/10.1038/s41551-021-00799-6 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms Reprints and permissions information is available at www.nature.com/reprints (http://www.nature.com/reprints) .
spellingShingle Article
Xue, Gang
Wang, Ziyu
Zheng, Ningbo
Fang, Jing
Mao, Chengqiong
Li, Xiaoyin
Jin, Guangxu
Ming, Xin
Lu, Yong
Elimination of acquired resistance to PD-1 blockade via the concurrent depletion of tumour cells and immunosuppressive cells
title Elimination of acquired resistance to PD-1 blockade via the concurrent depletion of tumour cells and immunosuppressive cells
title_full Elimination of acquired resistance to PD-1 blockade via the concurrent depletion of tumour cells and immunosuppressive cells
title_fullStr Elimination of acquired resistance to PD-1 blockade via the concurrent depletion of tumour cells and immunosuppressive cells
title_full_unstemmed Elimination of acquired resistance to PD-1 blockade via the concurrent depletion of tumour cells and immunosuppressive cells
title_short Elimination of acquired resistance to PD-1 blockade via the concurrent depletion of tumour cells and immunosuppressive cells
title_sort elimination of acquired resistance to pd-1 blockade via the concurrent depletion of tumour cells and immunosuppressive cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595849/
https://www.ncbi.nlm.nih.gov/pubmed/34725506
http://dx.doi.org/10.1038/s41551-021-00799-6
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