ScRNA-seq Unveils the Functional Characteristics of Glioma-associated Macrophages and the Regulatory Effects of Chlorogenic Acid on the Immune Microenvironment-a Study Based on Mouse Models and Clinical Practice

Overview

Journal Front Immunol

Date 2025 Jan 27

PMID 39867913

Authors

Jiachen Wang

Shenglan Li

Yuxiao Chen

Jinyi Chen

Can Wang

Zhuang Kang

Mengqian Huang

Zehao Cai

Yuxiang Fan

Yanjie Lan

Yumeng Yu

Ruijing Bai

Feng Chen

Jiandong Jiang

Wenbin Li

Affiliations

Soon will be listed here.

Abstract

Introduction: Glioma is the most common primary malignant brain tumor. Despite advances in surgical techniques and treatment regimens, the therapeutic effects of glioma remain unsatisfactory. Immunotherapy has brought new hope to glioma patients, but its therapeutic outcomes are limited by the immunosuppressive nature of the tumor microenvironment (TME). This study aimed to reveal the subpopulations and functional characteristics of tumor-associated macrophages (TAMs) and explore the regulatory effects of chlorogenic acid (CHA) on the immune microenvironment, as well as its potential for clinical application.

Methods: In this study, CHA was used in model mice. ScRNA - seq analysis was conducted to elucidate the differentiation trajectories and functional characteristics of bone marrow - derived monomacrophages (BMDMs) and microglia. A PPI and molecular docking model were constructed using the target prediction database. A case of a patient treated with CHA was reviewed.

Results: CHA slowed tumor growth in model mice and extended the survival time of mice. It enhanced the antigen - presenting function of macrophages and T - cell immune activation - related gene expression, activated microglia through the JAK - STAT pathway, and improved the antitumor functions. The good affinity of CHA with STAT1 was confirmed. The patient treated with CHA survived for 5 years and 6 months, achieved partial remission (PR) after 9 months of treatment, and remained alive without any new symptoms or toxic side effects. Our study revealed the subtypes and differentiation trajectories of TAMs. CHA significantly improved the immune microenvironment of glioma by modulating the function of BMDMs and microglia.

Discussion: This study may provide new insights into targeting the regulation of TME and offer theoretical and practical support for the clinical application of CHA. The results demonstrated the potential of CHA in improving the immune microenvironment and antitumor effects, which could have implications for future glioma treatment strategies.

References

Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S . The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Curr Protoc Bioinformatics. 2016; 54:1.30.1-1.30.33. DOI: 10.1002/cpbi.5. View

Skala E, Kowalczyk T, Toma M, Szemraj J, Radek M, Pytel D . Induction of apoptosis in human glioma cell lines of various grades through the ROS-mediated mitochondrial pathway and caspase activation by Rhaponticum carthamoides transformed root extract. Mol Cell Biochem. 2017; 445(1-2):89-97. DOI: 10.1007/s11010-017-3254-z. View

Skala E, Sitarek P, Toma M, Szemraj J, Radek M, Nieborowska-Skorska M . Inhibition of human glioma cell proliferation by altered Bax/Bcl-2-p53 expression and apoptosis induction by Rhaponticum carthamoides extracts from transformed and normal roots. J Pharm Pharmacol. 2016; 68(11):1454-1464. DOI: 10.1111/jphp.12619. View

Musca B, Russo M, Tushe A, Magri S, Battaggia G, Pinton L . The immune cell landscape of glioblastoma patients highlights a myeloid-enriched and immune suppressed microenvironment compared to metastatic brain tumors. Front Immunol. 2023; 14:1236824. PMC: 10626453. DOI: 10.3389/fimmu.2023.1236824. View

Nwafor E, Lu P, Zhang Y, Liu R, Peng H, Xing B . Chlorogenic acid: Potential source of natural drugs for the therapeutics of fibrosis and cancer. Transl Oncol. 2021; 15(1):101294. PMC: 8640119. DOI: 10.1016/j.tranon.2021.101294. View

Mutisheva I, Robatel S, Bariswyl L, Schenk M . An Innovative Approach to Tissue Processing and Cell Sorting of Fixed Cells for Subsequent Single-Cell RNA Sequencing. Int J Mol Sci. 2022; 23(18). PMC: 9499188. DOI: 10.3390/ijms231810233. View

Daina A, Michielin O, Zoete V . SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019; 47(W1):W357-W364. PMC: 6602486. DOI: 10.1093/nar/gkz382. View

Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck 3rd W . Comprehensive Integration of Single-Cell Data. Cell. 2019; 177(7):1888-1902.e21. PMC: 6687398. DOI: 10.1016/j.cell.2019.05.031. View

Huang S, Wang L, Xue N, Li C, Guo H, Ren T . Chlorogenic acid effectively treats cancers through induction of cancer cell differentiation. Theranostics. 2019; 9(23):6745-6763. PMC: 6815948. DOI: 10.7150/thno.34674. View

10.

Zheng G, Terry J, Belgrader P, Ryvkin P, Bent Z, Wilson R . Massively parallel digital transcriptional profiling of single cells. Nat Commun. 2017; 8:14049. PMC: 5241818. DOI: 10.1038/ncomms14049. View

11.

Huang J, Xie M, He L, Song X, Cao T . Chlorogenic acid: a review on its mechanisms of anti-inflammation, disease treatment, and related delivery systems. Front Pharmacol. 2023; 14:1218015. PMC: 10534970. DOI: 10.3389/fphar.2023.1218015. View

12.

Weller M, Wen P, Chang S, Dirven L, Lim M, Monje M . Glioma. Nat Rev Dis Primers. 2024; 10(1):33. DOI: 10.1038/s41572-024-00516-y. View

13.

Yin J, Valin K, Dixon M, Leavenworth J . The Role of Microglia and Macrophages in CNS Homeostasis, Autoimmunity, and Cancer. J Immunol Res. 2018; 2017:5150678. PMC: 5749282. DOI: 10.1155/2017/5150678. View

14.

Li R, Zhan Y, Ding X, Cui J, Han Y, Zhang J . Cancer Differentiation Inducer Chlorogenic Acid Suppresses PD-L1 Expression and Boosts Antitumor Immunity of PD-1 Antibody. Int J Biol Sci. 2024; 20(1):61-77. PMC: 10750284. DOI: 10.7150/ijbs.83599. View

15.

Ren T, Wang Y, Wang C, Zhang M, Huang W, Jiang J . Isolation and identification of human metabolites from a novel anti-tumor candidate drug 5-chlorogenic acid injection by HPLC-HRMS/MS and HPLC-SPE-NMR. Anal Bioanal Chem. 2017; 409(30):7035-7048. DOI: 10.1007/s00216-017-0657-3. View

16.

Kim S, Chen J, Cheng T, Gindulyte A, He J, He S . PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. 2020; 49(D1):D1388-D1395. PMC: 7778930. DOI: 10.1093/nar/gkaa971. View

17.

Yasinjan F, Xing Y, Geng H, Guo R, Yang L, Liu Z . Immunotherapy: a promising approach for glioma treatment. Front Immunol. 2023; 14:1255611. PMC: 10512462. DOI: 10.3389/fimmu.2023.1255611. View

18.

Ostrom Q, Price M, Neff C, Cioffi G, Waite K, Kruchko C . CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2016-2020. Neuro Oncol. 2023; 25(12 Suppl 2):iv1-iv99. PMC: 10550277. DOI: 10.1093/neuonc/noad149. View

19.

Gupta A, Atanasov A, Li Y, Kumar N, Bishayee A . Chlorogenic acid for cancer prevention and therapy: Current status on efficacy and mechanisms of action. Pharmacol Res. 2022; 186:106505. DOI: 10.1016/j.phrs.2022.106505. View

20.

Chin C, Chen S, Wu H, Ho C, Ko M, Lin C . cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol. 2014; 8 Suppl 4:S11. PMC: 4290687. DOI: 10.1186/1752-0509-8-S4-S11. View