Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism.

Publisher: Life Science Alliance, LLC Country of Publication: United States NLM ID: 101728869 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 2575-1077 (Electronic) Linking ISSN: 25751077 NLM ISO Abbreviation: Life Sci Alliance Subsets: MEDLINE

Original Publication: [Woodbury, NY] : Life Science Alliance, LLC, [2018]-

Arginine*/metabolism ; Breast Neoplasms*/metabolism ; Breast Neoplasms*/immunology ; Breast Neoplasms*/pathology ; Tumor-Associated Macrophages*/metabolism ; Tumor-Associated Macrophages*/immunology ; Tumor Microenvironment*/immunology ; Nitric Oxide*/metabolism; Female ; Humans ; Mice ; Animals ; Cellular Reprogramming ; Cell Line, Tumor ; Macrophages/metabolism ; Macrophages/immunology

HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor-associated macrophages (TAMs). Although TAMs consist of the immune-stimulatory M1 type and immune-suppressive M2 type, the M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1- versus M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2-TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- versus M2-TAMs is attributed to different availability of BH 4 (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH 4 precursor, elevates the expression of M1-TAM markers within HER2+ tumors. Here, we show that SEP restores BH 4 levels in M2-like macrophages, which then redirects arginine metabolism to NO synthesis and converts M2 type to M1 type. The reprogrammed macrophages exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in the metabolic shift of the HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.
(© 2024 Fernando et al.)

Update of: bioRxiv. 2023 Aug 22:2023.08.22.554238. doi: 10.1101/2023.08.22.554238. (PMID: 37662241)

Hum Mol Genet. 2016 Dec 1;25(23):5188-5197. (PMID: 27798097)
Mol Genet Metab. 2005 Dec;86 Suppl 1:S2-10. (PMID: 16256391)
Cell. 2021 Jun 24;184(13):3573-3587.e29. (PMID: 34062119)
BMB Rep. 2019 Jun;52(6):360-372. (PMID: 31186085)
Front Immunol. 2020 Dec 15;11:605958. (PMID: 33384693)
Biomark Res. 2021 Jan 6;9(1):1. (PMID: 33407885)
Metabolism. 2022 Mar;128:155116. (PMID: 34973284)
Immunology. 2001 May;103(1):41-8. (PMID: 11380691)
Invest Ophthalmol Vis Sci. 1985 May;26(5):768-70. (PMID: 3997425)
Nat Commun. 2021 Sep 1;12(1):5217. (PMID: 34471116)
Cell Rep. 2019 Jul 2;28(1):218-230.e7. (PMID: 31269442)
Nature. 2018 Nov;563(7732):564-568. (PMID: 30405245)
Elife. 2018 Mar 21;7:. (PMID: 29560860)
Postepy Hig Med Dosw (Online). 2015 Apr 22;69:496-502. (PMID: 25983288)
Int J Mol Sci. 2021 Jun 29;22(13):. (PMID: 34209703)
Elife. 2023 Feb 22;12:. (PMID: 36811599)
Am J Physiol Heart Circ Physiol. 2015 Nov 15;309(10):H1782-91. (PMID: 26408540)
Biomed Res Int. 2015;2015:341308. (PMID: 26366410)
Cancers (Basel). 2014 Aug 13;6(3):1670-90. (PMID: 25125485)
Cell Death Differ. 2014 Jan;21(1):79-91. (PMID: 23852373)
Front Immunol. 2017 Sep 07;8:1097. (PMID: 28936211)
Int J Cell Biol. 2012;2012:762825. (PMID: 22666258)
Pharmacol Res. 2020 Jul;157:104827. (PMID: 32348841)
Oncotarget. 2016 Aug 9;7(32):52294-52306. (PMID: 27418133)
Med Sci Monit Basic Res. 2017 Jan 26;23:8-19. (PMID: 28123171)
BMC Mol Biol. 2010 Dec 01;11:90. (PMID: 21122122)
Clin Exp Immunol. 2002 Feb;127(2):220-5. (PMID: 11876743)
Biochem Biophys Res Commun. 1994 Sep 30;203(3):1614-21. (PMID: 7945311)
Cell Metab. 2019 Aug 6;30(2):352-363.e8. (PMID: 31130465)
F1000Prime Rep. 2014 Mar 03;6:13. (PMID: 24669294)
Front Immunol. 2020 Dec 03;11:583084. (PMID: 33365025)
Sci Rep. 2019 Apr 30;9(1):6688. (PMID: 31040372)
Clin Cancer Res. 2008 Oct 1;14(19):6116-24. (PMID: 18829490)
PLoS One. 2017 Aug 17;12(8):e0183572. (PMID: 28817687)
Mol Genet Metab. 2019 Apr;126(4):406-412. (PMID: 30922814)
ChemTexts. 2022;8(2):12. (PMID: 35287314)
Immunology. 2003 Jul;109(3):384-91. (PMID: 12807484)
Signal Transduct Target Ther. 2021 Mar 26;6(1):127. (PMID: 33767177)
Sci Rep. 2016 Feb 12;6:21044. (PMID: 26869018)
Adv Exp Med Biol. 2016;899:211-29. (PMID: 27325269)
Circulation. 2011 Oct 25;124(17):1860-70. (PMID: 21969008)
J Innate Immun. 2014;6(6):716-26. (PMID: 25138714)
Cell Mol Immunol. 2016 Sep;13(5):628-39. (PMID: 26277898)
Biomark Res. 2020 Sep 29;8:49. (PMID: 33005420)
Breast Cancer (Dove Med Press). 2019 Jan 17;11:53-69. (PMID: 30697064)
Lupus Sci Med. 2019 Feb 19;6(1):e000294. (PMID: 31168396)
Blood. 2013 Aug 22;122(8):1411-8. (PMID: 23847195)
J Immunol. 2006 Nov 15;177(10):7303-11. (PMID: 17082649)
Biochemistry. 1999 Dec 14;38(50):16663-70. (PMID: 10600129)
Am J Respir Cell Mol Biol. 2015 Nov;53(5):676-88. (PMID: 25870903)
Sci Rep. 2017 Aug 21;7(1):8965. (PMID: 28827726)
Methods Mol Biol. 2019;1884:119-130. (PMID: 30465198)
Front Immunol. 2020 Aug 28;11:1613. (PMID: 32983083)
Food Funct. 2013 Feb;4(2):266-76. (PMID: 23135314)
Hum Pathol. 2007 Oct;38(10):1516-25. (PMID: 17640716)
Cancer Cell. 2018 Nov 12;34(5):757-774.e7. (PMID: 30423296)
Biochem Pharmacol. 2020 Jun;176:113887. (PMID: 32112882)
Proc Natl Acad Sci U S A. 1983 Mar;80(6):1546-50. (PMID: 6572916)
Int J Oncol. 2013 Jul;43(1):5-12. (PMID: 23673510)
Front Immunol. 2021 Jun 23;12:690869. (PMID: 34248982)
Biol Open. 2017 Dec 15;6(12):1897-1903. (PMID: 29162623)
Mol Cancer Res. 2015 Jun;13(6):1034-43. (PMID: 25724429)
Inflamm Res. 2013 Sep;62(9):865-9. (PMID: 23775039)
J Transl Med. 2011 Dec 16;9:216. (PMID: 22176642)
Antioxidants (Basel). 2023 May 03;12(5):. (PMID: 37237903)
Infect Drug Resist. 2019 Aug 22;12:2589-2611. (PMID: 31686866)
Front Immunol. 2014 Nov 28;5:614. (PMID: 25506346)
Nat Rev Immunol. 2018 Aug;18(8):527-535. (PMID: 29662120)
ACS Nano. 2022 Mar 22;16(3):3881-3894. (PMID: 35238549)
Nat Commun. 2017 Jan 16;8:14049. (PMID: 28091601)
Front Immunol. 2014 Oct 17;5:514. (PMID: 25368618)
Sci Rep. 2019 Jul 29;9(1):10961. (PMID: 31358801)
Cancers (Basel). 2021 Jun 05;13(11):. (PMID: 34198735)
Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):5914-5919. (PMID: 30850527)
Trends Cancer. 2022 Dec;8(12):980-987. (PMID: 35965200)
Molecules. 2018 Dec 20;24(1):. (PMID: 30577495)
Front Immunol. 2017 Feb 07;8:93. (PMID: 28223985)
Br J Pharmacol. 2003 Oct;140(4):701-6. (PMID: 14534153)

R01 CA248304 United States CA NCI NIH HHS; R21 CA288449 United States CA NCI NIH HHS

94ZLA3W45F (Arginine)
31C4KY9ESH (Nitric Oxide)

Date Created: 20240827 Date Completed: 20240827 Latest Revision: 20241220

20241220

PMC11350068

10.26508/lsa.202302339

39191486