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

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

  • Gut. 2023 Sep 28:gutjnl-2023-329543. doi: 10.1136/gutjnl-2023-329543.
Winnie Fong 1,  Qing Li 1 2,  Fenfen Ji 1,  Wei Liang 3,  Harry Cheuk Hay Lau 1,  Xing Kang 1,  Weixin Liu 1,  Kenneth Kin-Wah To 4,  Zhong Zuo 4,  Xiaoxing Li 3,  Xiang Zhang 1,  Joseph Jy Sung 5,  Jun Yu 6
Affiliations

Affiliations

  • 1 Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • 2 Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
  • 3 Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 4 School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, China.
  • 5 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
  • 6 Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China [email protected].
PMID: 37770127 DOI: 10.1136/gutjnl-2023-329543
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.

Keywords

colorectal cancer; immunotherapy; probiotics.

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