CPT1C-positive cancer-associated fibroblast facilitates immunosuppression through promoting IL-6-induced M2-like phenotype of macrophage.

Publisher: Taylor & Francis Country of Publication: United States NLM ID: 101570526 Publication Model: eCollection Cited Medium: Internet ISSN: 2162-402X (Electronic) Linking ISSN: 21624011 NLM ISO Abbreviation: Oncoimmunology Subsets: MEDLINE

Publication: 2015- : Philadelphia, PA : Taylor & Francis
Original Publication: Austin, TX : Landes Bioscience

Tumor Microenvironment*/immunology ; Carnitine O-Palmitoyltransferase*/genetics ; Carnitine O-Palmitoyltransferase*/metabolism ; Cancer-Associated Fibroblasts*/metabolism ; Cancer-Associated Fibroblasts*/immunology ; Cancer-Associated Fibroblasts*/pathology ; Interleukin-6*/metabolism ; Interleukin-6*/genetics ; Macrophages*/immunology ; Macrophages*/metabolism; Humans ; Stomach Neoplasms/immunology ; Stomach Neoplasms/pathology ; Stomach Neoplasms/genetics ; Stomach Neoplasms/metabolism ; Phenotype ; Animals ; Mice ; Male ; Female ; Cell Line, Tumor ; Immune Tolerance

Cancer-associated fibroblasts (CAFs) exhibit remarkable phenotypic heterogeneity, with specific subsets implicated in immunosuppression in various malignancies. However, whether and how they attenuate anti-tumor immunity in gastric cancer (GC) remains elusive. CPT1C, a unique isoform of carnitine palmitoyltransferase pivotal in regulating fatty acid oxidation, is briefly indicated as a protumoral metabolic mediator in the tumor microenvironment (TME) of GC. In the present study, we initially identified specific subsets of fibroblasts exclusively overexpressing CPT1C, hereby termed them as CPT1C ⁺ CAFs. Subsequent findings indicated that CPT1C ⁺ CAFs fostered a stroma-enriched and immunosuppressive TME as they correlated with extracellular matrix-related molecular features and enrichment of both immunosuppressive subsets, especially M2-like macrophages, and multiple immune-related pathways. Next, we identified that CPT1C ⁺ CAFs promoted the M2-like phenotype of macrophage in vitro . Bioinformatic analyses unveiled the robust IL-6 signaling between CPT1C ⁺ CAFs and M2-like phenotype of macrophage and identified CPT1C ⁺ CAFs as the primary source of IL-6. Meanwhile, suppressing CPT1C expression in CAFs significantly decreased IL-6 secretion in vitro . Lastly, we demonstrated the association of CPT1C ⁺ CAFs with therapeutic resistance. Notably, GC patients with high CPT1C ⁺ CAFs infiltration responded poorly to immunotherapy in clinical cohort. Collectively, our data not only present the novel identification of CPT1C ⁺ CAFs as immunosuppressive subsets in TME of GC, but also reveal the underlying mechanism that CPT1C ⁺ CAFs impair tumor immunity by secreting IL-6 to induce the immunosuppressive M2-like phenotype of macrophage in GC.
Competing Interests: No potential conflict of interest was reported by the author(s).
(© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Nat Commun. 2018 May 3;9(1):1777. (PMID: 29725014)
Biomark Res. 2021 Oct 9;9(1):72. (PMID: 34625124)
Gastric Cancer. 2017 Jan;20(1):92-103. (PMID: 26694715)
Nature. 2014 Sep 11;513(7517):202-9. (PMID: 25079317)
Oncotarget. 2017 Mar 28;8(13):20741-20750. (PMID: 28186964)
Lancet. 2020 Aug 29;396(10251):635-648. (PMID: 32861308)
Mol Cancer. 2019 Mar 18;18(1):42. (PMID: 30885232)
Cancer Immunol Immunother. 2017 Dec;66(12):1597-1608. (PMID: 28828629)
Cancer Cell. 2023 Aug 14;41(8):1407-1426.e9. (PMID: 37419119)
Clin Cancer Res. 2017 Aug 1;23(15):4441-4449. (PMID: 28747339)
Nat Commun. 2020 Oct 8;11(1):5077. (PMID: 33033240)
Cancer Treat Rev. 2020 Jun;86:102015. (PMID: 32248000)
Genes Dev. 2011 May 15;25(10):1041-51. (PMID: 21576264)
J Biomed Sci. 2019 Oct 20;26(1):78. (PMID: 31629410)
Nat Commun. 2023 Nov 10;14(1):7286. (PMID: 37949861)
Nat Commun. 2018 Feb 8;9(1):559. (PMID: 29422647)
Cell Death Dis. 2023 Jan 24;14(1):57. (PMID: 36693836)
Front Oncol. 2021 Jul 14;11:668349. (PMID: 34336660)
Eur J Cancer. 2016 Jul;62:138-45. (PMID: 27237360)
J Transl Med. 2021 Jul 31;19(1):325. (PMID: 34332586)
Mol Oncol. 2021 May;15(5):1391-1411. (PMID: 33528867)
Nat Rev Drug Discov. 2019 Feb;18(2):99-115. (PMID: 30470818)
Immunol Rev. 2021 Jul;302(1):241-258. (PMID: 34075584)
Acta Biochim Biophys Sin (Shanghai). 2022 May 25;54(5):752-755. (PMID: 35593464)
Cancers (Basel). 2023 Jul 05;15(13):. (PMID: 37444617)
Gastric Cancer. 2017 May;20(3):438-447. (PMID: 27318497)
Front Pharmacol. 2021 Oct 26;12:760581. (PMID: 34764874)
Nat Med. 2018 Sep;24(9):1449-1458. (PMID: 30013197)
Life Sci. 2020 Oct 1;258:118110. (PMID: 32698074)
Trends Cancer. 2023 May;9(5):421-443. (PMID: 36870916)
J Gastrointest Oncol. 2020 Aug;11(4):695-707. (PMID: 32953153)
Cell Rep. 2014 Oct 9;9(1):349-365. (PMID: 25263561)
Int J Biol Sci. 2022 Feb 21;18(5):1912-1932. (PMID: 35342344)
Biochem Biophys Res Commun. 2012 Jun 22;423(1):60-6. (PMID: 22634002)
Mol Cancer. 2019 Mar 30;18(1):68. (PMID: 30927911)
Oncogene. 2019 Jun;38(25):4887-4901. (PMID: 30816343)
Nat Commun. 2023 Jul 17;14(1):4251. (PMID: 37460545)
J Hematol Oncol. 2023 May 27;16(1):57. (PMID: 37245017)
Cell Death Dis. 2016 May 19;7:e2226. (PMID: 27195673)
Immunity. 2014 Jul 17;41(1):14-20. (PMID: 25035950)
Ann Oncol. 2020 Aug;31(8):1011-1020. (PMID: 32387455)
J Clin Med. 2023 Apr 01;12(7):. (PMID: 37048719)
Theranostics. 2022 Jan 1;12(2):620-638. (PMID: 34976204)
Cell Stem Cell. 2012 Dec 7;11(6):812-24. (PMID: 23168163)
Nat Commun. 2022 Nov 4;13(1):6619. (PMID: 36333338)
Mol Cancer. 2021 Oct 11;20(1):131. (PMID: 34635121)
Cancer Discov. 2022 Mar 1;12(3):670-691. (PMID: 34642171)
J Hematol Oncol. 2019 Jul 12;12(1):76. (PMID: 31300030)
Prog Lipid Res. 2016 Jan;61:134-48. (PMID: 26708865)
Elife. 2020 Dec 28;9:. (PMID: 33370234)
Mol Cancer. 2023 Oct 2;22(1):159. (PMID: 37784082)
Clin Cancer Res. 2018 Oct 1;24(19):4820-4833. (PMID: 29921731)
J Oncol. 2019 Jun 9;2019:6270784. (PMID: 31281359)
Clin Cancer Res. 2018 Nov 1;24(21):5407-5421. (PMID: 29959142)
Cancer Immunol Immunother. 2023 Jul;72(7):2029-2044. (PMID: 36764954)
Front Immunol. 2023 Jun 05;14:1194642. (PMID: 37342322)
Cell Rep. 2021 Nov 2;37(5):109955. (PMID: 34731634)

Keywords: Carnitine palmitoyltransferase 1C; M2-like macrophage; cancer-associated fibroblast; gastric cancer; immunosuppression; interleukin 6

Date Created: 20240515 Date Completed: 20240515 Latest Revision: 20240603

20240604

PMC11093039

10.1080/2162402X.2024.2352179

38746869