<i>Lactobacillus gallinarum</i>-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis

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Abstract

Objective

Gut microbiota is a key player in dictating immunotherapy response. We aimed to explore the immunomodulatory effect of probiotic Lactobacillus gallinarum and its role in improving anti-programmed cell death protein 1 (PD1) efficacy against colorectal cancer (CRC).

Design

The effects of L. gallinarum in anti-PD1 response were assessed in syngeneic mouse models and azoxymethane/dextran sulfate sodium-induced CRC model. The change of immune landscape was identified by multicolour flow cytometry and validated by immunohistochemistry staining and in vitro functional assays. Liquid chromatography-mass spectrometry was performed to identify the functional metabolites.

Results

L. gallinarum significantly improved anti-PD1 efficacy in two syngeneic mouse models with different microsatellite instability (MSI) statuses (MSI-high for MC38, MSI-low for CT26). Such effect was confirmed in CRC tumourigenesis model. L. gallinarum synergised with anti-PD1 therapy by reducing Foxp3 ⁺ CD25 ⁺ regulatory T cell (Treg) intratumoural infiltration, and enhancing effector function of CD8 ⁺ T cells. L. gallinarum-derived indole-3-carboxylic acid (ICA) was identified as the functional metabolite. Mechanistically, ICA inhibited indoleamine 2,3-dioxygenase (IDO1) expression, therefore suppressing kynurenine (Kyn) production in tumours. ICA also competed with Kyn for binding site on aryl hydrocarbon receptor (AHR) and antagonised Kyn binding on CD4 ⁺ T cells, thereby inhibiting Treg differentiation in vitro. ICA phenocopied L. gallinarum effect and significantly improved anti-PD1 efficacy in vivo, which could be reversed by Kyn supplementation.

Conclusion

L. gallinarum-derived ICA improved anti-PD1 efficacy in CRC through suppressing CD4+Treg differentiation and enhancing CD8+T cell function by modulating the IDO1/Kyn/AHR axis. L. gallinarum is a potential adjuvant to augment anti-PD1 efficacy against CRC.

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Most cited references 45

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Cancer immunotherapy using checkpoint blockade

Jedd Wolchok, Antoni Ribas (2018)

The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte antigen-4 (CTLA-4) or the programmed death-1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the pre-existence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long lasting disease control, yet one third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon gamma signaling pathways. New generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.

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Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors

Bo Qu, Gladys Ferrere, Céline Clemenson … (2018)

Immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizeable minority of cancer patients. Here, we show that primary resistance to ICI can be due to abnormal gut microbiome composition. Antibiotics (ATB) inhibited the clinical benefit of ICI in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICI (but not from non-responding patients) into germ-free or ATB-treated mice ameliorated the antitumor effects of PD-1 blockade. Metagenomics of patient stools at diagnosis revealed correlations between clinical responses to ICI and the relative abundance of Akkermansia muciniphila. Oral supplementation with A. muciniphila post-FMT with non-responder feces restored the efficacy of PD-1 blockade in an IL-12-dependent manner, by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into tumor beds.

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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

Journal

Journal ID (nlm-ta): Gut

Journal ID (iso-abbrev): Gut

Journal ID (hwp): gutjnl

Journal ID (publisher-id): gut

Title: Gut

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0017-5749

ISSN (Electronic): 1468-3288

Publication date (Print): December 2023

Publication date (Electronic): 28 September 2023

Volume: 72

Issue: 12

Pages: 2272-2285

Affiliations

[1 ] departmentInstitute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences , Ringgold_26451The Chinese University of Hong Kong , Hong Kong, China

[2 ] departmentDepartment of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute , The Chinese University of Hong Kong , Hong Kong, China

[3 ] departmentInstitute of Precision Medicine , Ringgold_71068The First Affiliated Hospital of Sun Yat-Sen University , Guangzhou, China

[4 ] departmentSchool of Pharmacy , Ringgold_26451The Chinese University of Hong Kong , Hong Kong, China

[5 ] departmentLee Kong Chian School of Medicine , Ringgold_54761Nanyang Technological University , Singapore

Author notes

[Correspondence to ] Professor Jun Yu, Institute of Digestive Disease, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; junyu@ 123456cuhk.edu.hk

Author information

Harry Cheuk Hay Lau http://orcid.org/0000-0003-3581-2909

Xiaoxing Li http://orcid.org/0000-0001-8791-7505

Joseph JY Sung http://orcid.org/0000-0003-3125-5199

Jun Yu http://orcid.org/0000-0001-5008-2153

Article

Publisher ID: gutjnl-2023-329543

DOI: 10.1136/gutjnl-2023-329543

PMC ID: 10715476

PubMed ID: 37770127

SO-VID: 12aa38d7-a881-4f00-ae1b-2b65dc90cb65

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 19 January 2023

Date accepted : 16 August 2023

Funding

Funded by: Shenzhen-Hong Kong-Macao Science and Technology Program (Category C) Shenzhen;

Award ID: SGDX20210823103535016

Funded by: Research Talent Hub-Innovation and Technology Fund Hong Kong;

Award ID: ITS/177/21FP

Funded by: RGC Research Impact Fund Hong Kong;

Award ID: R4032-21F

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ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: probiotics,immunotherapy,colorectal cancer

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ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: probiotics, immunotherapy, colorectal cancer

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Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis

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Abstract

Objective

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Karger: Gastroenterology

Most cited references 45

Cancer immunotherapy using checkpoint blockade

Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors

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

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