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Correction of arginine metabolism with sepiapterin—the precursor of nitric oxide synthase cofactor BH(4)—induces immunostimulatory-shift of breast cancer

Immunotherapy is a first-line treatment for many tumor types. However, most breast tumors are immunosuppressive and only modestly respond to immunotherapy. We hypothesized that correcting arginine metabolism might improve the immunogenicity of breast tumors. We tested whether supplementing sepiapter...

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Autores principales: Zheng, Xunzhen, Fernando, Veani, Sharma, Vandana, Walia, Yashna, Letson, Joshua, Furuta, Saori
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842273/
https://www.ncbi.nlm.nih.gov/pubmed/32112882
http://dx.doi.org/10.1016/j.bcp.2020.113887
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author Zheng, Xunzhen
Fernando, Veani
Sharma, Vandana
Walia, Yashna
Letson, Joshua
Furuta, Saori
author_facet Zheng, Xunzhen
Fernando, Veani
Sharma, Vandana
Walia, Yashna
Letson, Joshua
Furuta, Saori
author_sort Zheng, Xunzhen
collection PubMed
description Immunotherapy is a first-line treatment for many tumor types. However, most breast tumors are immunosuppressive and only modestly respond to immunotherapy. We hypothesized that correcting arginine metabolism might improve the immunogenicity of breast tumors. We tested whether supplementing sepiapterin, the precursor of tetrahydrobiopterin (BH(4))—the nitric oxide synthase (NOS) cofactor—redirects arginine metabolism from the pathway synthesizing polyamines to that of synthesizing nitric oxide (NO) and make breast tumors more immunogenic. We showed that sepiapterin elevated NO but lowered polyamine levels in tumor cells, as well as in tumor-associated macrophages (TAMs). This not only suppressed tumor cell proliferation, but also induced the conversion of TAMs from the immuno-suppressive M2-type to immuno-stimulatory M1-type. Furthermore, sepiapterin abrogated the expression of a checkpoint ligand, PD-L1, in tumors in a STAT3-dependent manner. This is the first study which reveals that supplementing sepiapterin normalizes arginine metabolism, improves the immunogenicity and inhibits the growth of breast tumor cells.
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spelling pubmed-78422732021-01-28 Correction of arginine metabolism with sepiapterin—the precursor of nitric oxide synthase cofactor BH(4)—induces immunostimulatory-shift of breast cancer Zheng, Xunzhen Fernando, Veani Sharma, Vandana Walia, Yashna Letson, Joshua Furuta, Saori Biochem Pharmacol Article Immunotherapy is a first-line treatment for many tumor types. However, most breast tumors are immunosuppressive and only modestly respond to immunotherapy. We hypothesized that correcting arginine metabolism might improve the immunogenicity of breast tumors. We tested whether supplementing sepiapterin, the precursor of tetrahydrobiopterin (BH(4))—the nitric oxide synthase (NOS) cofactor—redirects arginine metabolism from the pathway synthesizing polyamines to that of synthesizing nitric oxide (NO) and make breast tumors more immunogenic. We showed that sepiapterin elevated NO but lowered polyamine levels in tumor cells, as well as in tumor-associated macrophages (TAMs). This not only suppressed tumor cell proliferation, but also induced the conversion of TAMs from the immuno-suppressive M2-type to immuno-stimulatory M1-type. Furthermore, sepiapterin abrogated the expression of a checkpoint ligand, PD-L1, in tumors in a STAT3-dependent manner. This is the first study which reveals that supplementing sepiapterin normalizes arginine metabolism, improves the immunogenicity and inhibits the growth of breast tumor cells. 2020-02-27 2020-06 /pmc/articles/PMC7842273/ /pubmed/32112882 http://dx.doi.org/10.1016/j.bcp.2020.113887 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Zheng, Xunzhen
Fernando, Veani
Sharma, Vandana
Walia, Yashna
Letson, Joshua
Furuta, Saori
Correction of arginine metabolism with sepiapterin—the precursor of nitric oxide synthase cofactor BH(4)—induces immunostimulatory-shift of breast cancer
title Correction of arginine metabolism with sepiapterin—the precursor of nitric oxide synthase cofactor BH(4)—induces immunostimulatory-shift of breast cancer
title_full Correction of arginine metabolism with sepiapterin—the precursor of nitric oxide synthase cofactor BH(4)—induces immunostimulatory-shift of breast cancer
title_fullStr Correction of arginine metabolism with sepiapterin—the precursor of nitric oxide synthase cofactor BH(4)—induces immunostimulatory-shift of breast cancer
title_full_unstemmed Correction of arginine metabolism with sepiapterin—the precursor of nitric oxide synthase cofactor BH(4)—induces immunostimulatory-shift of breast cancer
title_short Correction of arginine metabolism with sepiapterin—the precursor of nitric oxide synthase cofactor BH(4)—induces immunostimulatory-shift of breast cancer
title_sort correction of arginine metabolism with sepiapterin—the precursor of nitric oxide synthase cofactor bh(4)—induces immunostimulatory-shift of breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842273/
https://www.ncbi.nlm.nih.gov/pubmed/32112882
http://dx.doi.org/10.1016/j.bcp.2020.113887
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