d-lactate modulates M2 tumor-associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma

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Abstract

The polarization of tumor-associated macrophages (TAMs) from M2 to M1 phenotype demonstrates great potential for remodeling the immunosuppressive tumor microenvironment (TME) of hepatocellular carcinoma (HCC). d-lactate (DL; a gut microbiome metabolite) acts as an endogenous immunomodulatory agent that enhances Kupffer cells for clearance of pathogens. In this study, the potential of DL for transformation of M2 TAMs to M1 was confirmed, and the mechanisms underlying such polarization were mainly due to the modulation of phosphatidylinositol 3-kinase/protein kinase B pathway. A poly(lactide- co-glycolide) nanoparticle (NP) was used to load DL, and the DL-loaded NP was modified with HCC membrane and M2 macrophage-binding peptide (M2pep), forming a nanoformulation (DL@NP-M-M2pep). DL@NP-M-M2pep transformed M2 TAMs to M1 and remodeled the immunosuppressive TME in HCC mice, promoting the efficacy of anti-CD47 antibody for long-term animal survival. These findings reveal a potential TAM modulatory function of DL and provide a combinatorial strategy for HCC immunotherapy.

Abstract

Modulation of M2 tumor-associated macrophages by a D-lactate nanoformulation promotes immunotherapy for liver cancer.

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Most cited references 80

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.

Garrett M Morris, Ruth Huey, William Lindstrom … (2009)

We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique. (c) 2009 Wiley Periodicals, Inc.

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Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients

J. Wargo, M Davies, J E Gershenwald … (2018)

Pre-clinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-PD-1 immunotherapy (n=112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders (R) versus non-responders (NR). Analysis of patient fecal microbiome samples (n=43, 30R, 13NR) showed significantly higher alpha diversity (p<0.01) and relative abundance of Ruminococcaceae bacteria (p<0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in R including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and anti-tumor immunity in responding patients with a favorable gut microbiome, as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

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Author and article information

Contributors

Shulan Han:

ORCID: https://orcid.org/0009-0000-7781-3200

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draft

Xueying Bao:

ORCID: https://orcid.org/0000-0002-4449-3922

Role: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: Visualization

Yifang Zou:

ORCID: https://orcid.org/0000-0002-4767-0808

Role: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: Visualization

Lingzhi Wang:

ORCID: https://orcid.org/0000-0002-9501-8566

Role: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: Visualization

Yutong Li: Role: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: Visualization

Leilei Yang: Role: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: Visualization

Anqi Liao: Role: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: Visualization

Xuemei Zhang: Role: Formal analysisRole: Investigation

Xin Jiang: Role: Data curationRole: Formal analysisRole: InvestigationRole: Resources

Di Liang: Role: Formal analysisRole: InvestigationRole: ResourcesRole: ValidationRole: Visualization

Yun Dai:

ORCID: https://orcid.org/0000-0003-2285-0818

Role: ConceptualizationRole: Resources

Qing-Chuan Zheng:

ORCID: https://orcid.org/0000-0003-2978-768X

Role: ConceptualizationRole: ValidationRole: Writing - original draftRole: Writing - review & editing

Zhuo Yu:

ORCID: https://orcid.org/0000-0003-4100-8415

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - review & editing

Jianfeng Guo:

ORCID: https://orcid.org/0000-0002-2893-912X

Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: July 2023

Publication date (Electronic, pub): 19 July 2023

Volume: 9

Issue: 29

Electronic Location Identifier: eadg2697

Affiliations

[ ¹ ]School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.

[ ² ]Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China.

[ ³ ]Department of Hepatopathy, Shuguang Hospital, affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

[ ⁴ ]Laboratory of Cancer Precision Medicine, The First Hospital of Jilin University, Changchun 130021, China.

[ ⁵ ]Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China.

[ ⁶ ]Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130012, China.

Author notes

[* ]Corresponding author. Email: jguo@ 123456jlu.edu.cn (J.G.); zhuoyu@ 123456shutcm.edu.cn (Z.Y.)

Author information

Shulan Han https://orcid.org/0009-0000-7781-3200

Xueying Bao https://orcid.org/0000-0002-4449-3922

Yifang Zou https://orcid.org/0000-0002-4767-0808

Lingzhi Wang https://orcid.org/0000-0002-9501-8566

Yun Dai https://orcid.org/0000-0003-2285-0818

Qing-Chuan Zheng https://orcid.org/0000-0003-2978-768X

Zhuo Yu https://orcid.org/0000-0003-4100-8415

Jianfeng Guo https://orcid.org/0000-0002-2893-912X

Article

Publisher ID: adg2697

DOI: 10.1126/sciadv.adg2697

PMC ID: 10355835

PubMed ID: 37467325

SO-VID: eb8eed03-d858-4355-9bc1-7858b28b80d0

Copyright © Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 13 December 2022

Date accepted : 16 June 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 82222074, 82074154 and 81774240

Funded by: Norman Bethune Program of Jilin University;

Award ID: 2022B40

Funded by: “Medicine + X” Interdisciplinary Innovation Team of Norman Bethune Health Science Center of Jilin University;

Award ID: 2022JBGS05

Funded by: Science and Technology Department of Jilin Province;

Award ID: 20230402044GH

Funded by: Science and Technology Department of Jilin Province;

Award ID: 20230101170JC

Funded by: Siming Scholar from Shanghai Shuguang Hospital;

Award ID: SGXZ-201904

Funded by: Youth Tip-top Talent Program from Shanghai Municipal Commission of Health;

Award ID: N/A

Funded by: Constant-eminent Program from Shanghai Municipal Commission of Health;

Award ID: N/A

Funded by: Xinglin Youth Scholar from Shanghai University of Traditional Chinese Medicine;

Award ID: N/A

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d-lactate modulates M2 tumor-associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma

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Most cited references 80

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.

Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients

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Cited by 24

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