Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma

Immunotherapy has demonstrated significant activity in a broad range of cancer types, but still the majority of patients receiving it do not maintain durable therapeutic responses. Amino acid metabolism has been proposed to be involved in the regulation of immune response. Here, we investigated in d...

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Autores principales:	Anna Sosnowska, Justyna Chlebowska-Tuz, Pawel Matryba, Zofia Pilch, Alan Greig, Artur Wolny, Tomasz M. Grzywa, Zuzanna Rydzynska, Olga Sokolowska, Tomasz P. Rygiel, Marcin Grzybowski, Paulina Stanczak, Roman Blaszczyk, Dominika Nowis, Jakub Golab
Formato:	article
Lenguaje:	EN
Publicado:	Taylor & Francis Group 2021
Materias:	arginase tumor microenvironment immunosuppression arginase inhibitor immunotherapy t-cells response myeloid cells Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/07d158283324431ba6734d685c57a6a0
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spelling	oai:doaj.org-article:07d158283324431ba6734d685c57a6a02021-11-11T14:23:43ZInhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma2162-402X10.1080/2162402X.2021.1956143https://doaj.org/article/07d158283324431ba6734d685c57a6a02021-01-01T00:00:00Zhttp://dx.doi.org/10.1080/2162402X.2021.1956143https://doaj.org/toc/2162-402XImmunotherapy has demonstrated significant activity in a broad range of cancer types, but still the majority of patients receiving it do not maintain durable therapeutic responses. Amino acid metabolism has been proposed to be involved in the regulation of immune response. Here, we investigated in detail the role of arginase 1 (Arg1) in the modulation of antitumor immune response against poorly immunogenic Lewis lung carcinoma. We observed that tumor progression is associated with an incremental increase in the number of Arg1+ myeloid cells that accumulate in the tumor microenvironment and cause systemic depletion of ʟ-arginine. In advanced tumors, the systemic concentrations of ʟ-arginine are decreased to levels that impair the proliferation of antigen-specific T-cells. Systemic or myeloid-specific Arg1 deletion improves antigen-induced proliferation of adoptively transferred T-cells and leads to inhibition of tumor growth. Arginase inhibitor was demonstrated to modestly inhibit tumor growth when used alone, and to potentiate antitumor effects of anti-PD-1 monoclonal antibodies and STING agonist. The effectiveness of the combination immunotherapy was insufficient to induce complete antitumor responses, but was significantly better than treatment with the checkpoint inhibitor alone. Together, these results indicate that arginase inhibition alone is of modest therapeutic benefit in poorly immunogenic tumors; however, in combination with other treatment strategies it may significantly improve survival outcomes.Anna SosnowskaJustyna Chlebowska-TuzPawel MatrybaZofia PilchAlan GreigArtur WolnyTomasz M. GrzywaZuzanna RydzynskaOlga SokolowskaTomasz P. RygielMarcin GrzybowskiPaulina StanczakRoman BlaszczykDominika NowisJakub GolabTaylor & Francis Grouparticlearginasetumor microenvironmentimmunosuppressionarginase inhibitorimmunotherapyt-cells responsemyeloid cellsImmunologic diseases. AllergyRC581-607Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENOncoImmunology, Vol 10, Iss 1 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	arginase tumor microenvironment immunosuppression arginase inhibitor immunotherapy t-cells response myeloid cells Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	arginase tumor microenvironment immunosuppression arginase inhibitor immunotherapy t-cells response myeloid cells Immunologic diseases. Allergy RC581-607 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Anna Sosnowska Justyna Chlebowska-Tuz Pawel Matryba Zofia Pilch Alan Greig Artur Wolny Tomasz M. Grzywa Zuzanna Rydzynska Olga Sokolowska Tomasz P. Rygiel Marcin Grzybowski Paulina Stanczak Roman Blaszczyk Dominika Nowis Jakub Golab Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma
description	Immunotherapy has demonstrated significant activity in a broad range of cancer types, but still the majority of patients receiving it do not maintain durable therapeutic responses. Amino acid metabolism has been proposed to be involved in the regulation of immune response. Here, we investigated in detail the role of arginase 1 (Arg1) in the modulation of antitumor immune response against poorly immunogenic Lewis lung carcinoma. We observed that tumor progression is associated with an incremental increase in the number of Arg1+ myeloid cells that accumulate in the tumor microenvironment and cause systemic depletion of ʟ-arginine. In advanced tumors, the systemic concentrations of ʟ-arginine are decreased to levels that impair the proliferation of antigen-specific T-cells. Systemic or myeloid-specific Arg1 deletion improves antigen-induced proliferation of adoptively transferred T-cells and leads to inhibition of tumor growth. Arginase inhibitor was demonstrated to modestly inhibit tumor growth when used alone, and to potentiate antitumor effects of anti-PD-1 monoclonal antibodies and STING agonist. The effectiveness of the combination immunotherapy was insufficient to induce complete antitumor responses, but was significantly better than treatment with the checkpoint inhibitor alone. Together, these results indicate that arginase inhibition alone is of modest therapeutic benefit in poorly immunogenic tumors; however, in combination with other treatment strategies it may significantly improve survival outcomes.
format	article
author	Anna Sosnowska Justyna Chlebowska-Tuz Pawel Matryba Zofia Pilch Alan Greig Artur Wolny Tomasz M. Grzywa Zuzanna Rydzynska Olga Sokolowska Tomasz P. Rygiel Marcin Grzybowski Paulina Stanczak Roman Blaszczyk Dominika Nowis Jakub Golab
author_facet	Anna Sosnowska Justyna Chlebowska-Tuz Pawel Matryba Zofia Pilch Alan Greig Artur Wolny Tomasz M. Grzywa Zuzanna Rydzynska Olga Sokolowska Tomasz P. Rygiel Marcin Grzybowski Paulina Stanczak Roman Blaszczyk Dominika Nowis Jakub Golab
author_sort	Anna Sosnowska
title	Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma
title_short	Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma
title_full	Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma
title_fullStr	Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma
title_full_unstemmed	Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma
title_sort	inhibition of arginase modulates t-cell response in the tumor microenvironment of lung carcinoma
publisher	Taylor & Francis Group
publishDate	2021
url	https://doaj.org/article/07d158283324431ba6734d685c57a6a0
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Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma

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