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

被引：126

作者：

Fong, Winnie ^{[1
]}

Li, Qing ^{[1
,2
,3
]}

Ji, Fenfen ^{[1
]}

Liang, Wei ^{[4
]}

Lau, Harry Cheuk Hay ^{[1
]}

Kang, Xing ^{[1
]}

Liu, Weixin ^{[1
]}

To, Kenneth Kin-Wah ^{[5
]}

Zuo, Zhong ^{[5
]}

Li, Xiaoxing ^{[4
]}

Zhang, Xiang ^{[1
]}

Sung, Joseph J. Y. ^{[6
]}

Yu, Jun ^{[1
,7
]}

机构：

[1] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Dept Med & Therapeut, State Key Lab Digest Dis,Inst Digest Dis, Hong Kong, Peoples R China

[2] Chinese Univ Hong Kong, Dept Anaesthesia & Intens Care, Hong Kong, Peoples R China

[3] Chinese Univ Hong Kong, Peter Hung Pain Res Inst, Hong Kong, Peoples R China

[4] Sun Yat Sen Univ, Affiliated Hosp 1, Inst Precis Med, Guangzhou, Peoples R China

[5] Chinese Univ Hong Kong, Sch Pharm, Hong Kong, Peoples R China

[6] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore

[7] Chinese Univ Hong Kong, Prince Wales Hosp, Inst Digest Dis, Dept Med & Therapeut, Hong Kong, Peoples R China

来源：

GUT | 2023年 / 72卷 / 12期

关键词：

probiotics; immunotherapy; colorectal cancer; ARYL-HYDROCARBON RECEPTOR; TRYPTOPHAN; KYNURENINE; RESISTANCE; COLITIS; AGONIST;

D O I：

10.1136/gutjnl-2023-329543

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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.

引用

页码：2272 / 2285

页数：14

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