Fungal mycobiome drives IL-33 secretion and type 2 immunity in pancreatic cancer

被引：218

作者：

Alam, Aftab ^{[1
]}

Levanduski, Eric ^{[1
]}

Denz, Parker ^{[1
]}

Villavicencio, Helena Solleiro ^{[1
,13
]}

Bhatta, Maulasri ^{[1
]}

Alhorebi, Lamees ^{[1
]}

Zhang, Yali ^{[2
]}

Gomez, Eduardo Cortes ^{[2
]}

Morreale, Brian ^{[1
]}

Senchanthisai, Sharon ^{[1
]}

Li, Jun ^{[3
]}

Turowski, Steven G. ^{[4
]}

Sexton, Sandra ^{[5
]}

Sait, Sheila Jani ^{[6
]}

Singh, Prashant K. ^{[7
]}

Wang, Jianmin ^{[2
]}

Maitra, Anirban ^{[8
]}

Kalinski, Pawel ^{[1
,9
]}

DePinho, Ronald A. ^{[10
]}

Wang, Huamin ^{[11
]}

Liao, Wenting ^{[12
]}

Abrams, Scott I. ^{[1
]}

Segal, Brahm H. ^{[9
]}

Dey, Prasenjit ^{[1
]}

机构：

[1] Roswell Pk Comprehens Canc Ctr, Dept Immunol, Elm & Carlton Sts CGP BLSC-L5307, Buffalo, NY 14263 USA

[2] Roswell Pk Comprehens Canc Ctr, Dept Biostat & Bioinformat, Buffalo, NY 14263 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[4] Roswell Pk Comprehens Canc Ctr, Dept Cell Stress Biol, Buffalo, NY 14263 USA

[5] Roswell Pk Comprehens Canc Ctr, Dept Anim Resources, Buffalo, NY 14263 USA

[6] Roswell Pk Comprehens Canc Ctr, Dept Cytogenet, Buffalo, NY 14263 USA

[7] Roswell Pk Comprehens Canc Ctr, Dept Canc Genet & Genom, Genom Shared Resource, Buffalo, NY 14263 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[9] Roswell Pk Comprehens Canc Ctr, Dept Med, Buffalo, NY 14263 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[12] Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Guangzhou 510060, Peoples R China

[13] Univ Autonoma Ciudad, Posgrad Ciencias Genom, Mexico City 06720, DF, Mexico

来源：

CANCER CELL | 2022年 / 40卷 / 02期

关键词：

INNATE; CELLS; INTERLEUKIN-33; RECEPTOR; KRAS; ST2; IDENTIFICATION; INFLAMMATION; MICROBIOME; INDUCTION;

D O I：

10.1016/j.ccell.2022.01.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

TH2 cells and innate lymphoid cells 2 (ILC2) can stimulate tumor growth by secreting pro-tumorigenic cytokines such as interleukin-4 (IL-4), IL-5, and IL-13. However, the mechanisms by which type 2 immune cells traffic to the tumor microenvironment are unknown. Here, we show that oncogenic Kras(G12D) increases IL 33 expression in pancreatic ductal adenocarcinoma (PDAC) cells, which recruits and activates TH2 and ILC2 cells. Correspondingly, cancer-cell-specific deletion of IL-33 reduces TH2 and ILC2 recruitment and promotes tumor regression. Unexpectedly, IL-33 secretion is dependent on the intratumoral fungal mycobiome. Genetic deletion of IL-33 or anti-fungal treatment decreases TH2 and ILC2 infiltration and increases survival. Consistently, high IL-33 expression is observed in approximately 20% of human PDAC, and expression is mainly restricted to cancer cells. These data expand our knowledge of the mechanisms driving PDAC tumor progression and identify therapeutically targetable pathways involving intratumoral mycobiome-driven secretion of IL-33.

引用

页码：153 / +

页数：27

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