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

Winnie Fong(Chinese University of Hong Kong), Qing Li(Chinese University of Hong Kong), Fenfen Ji(Chinese University of Hong Kong), Wei Liang(Sun Yat-sen University), Harry Cheuk-Hay Lau(Chinese University of Hong Kong), Xing Kang(Chinese University of Hong Kong), Weixin Liu(Chinese University of Hong Kong), Kenneth K.W. To(Chinese University of Hong Kong), Zhong Zuo(Chinese University of Hong Kong), Xiaoxing Li(Sun Yat-sen University), Xiang Zhang(Chinese University of Hong Kong), Joseph J.�Y. Sung(Nanyang Technological University), Jun Yu(Chinese University of Hong Kong)
Gut
September 28, 2023
10.1136/gutjnl-2023-329543
Cited by 259Open Access
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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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