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

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.

• Authors: Winnie Fong, Qing Li, Fenfen Ji, Wei Liang, Harry Cheuk Hay Lau, Xing Kang, Weixin Liu, Kenneth Kin-Wah To, Zhong Zuo, Xiaoxing Li, Xiang Zhang, Joseph Jy Sung, Jun Yu
• Journal: Gut (Gut) Vol. 72 Issue 12 Pg. 2272-2285 (Nov 24 2023) ISSN: 1468-3288 [Electronic] England
• PMID: 37770127 (Publication Type: Journal Article)
• Copyright: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Kynurenine
• Receptors, Aryl Hydrocarbon
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Immune Checkpoint Inhibitors
• IDO1 protein, mouse
• Bacterial Lysates

Topics

• Animals
• Mice
• CD8-Positive T-Lymphocytes
• Colorectal Neoplasms (drug therapy)
• Kynurenine (metabolism)
• Receptors, Aryl Hydrocarbon (drug effects, metabolism)
• T-Lymphocytes, Regulatory
• Lactobacillus (chemistry)
• Programmed Cell Death 1 Receptor (drug effects, immunology)
• Immune Checkpoint Inhibitors (pharmacology, therapeutic use)
• Bacterial Lysates (pharmacology, therapeutic use)