美国罗斯韦尔公园综合癌症中心Prasenjit Dey课题组发现，胰腺癌中真菌菌群驱动IL-33分泌和2型免疫。该项研究成果于2022年2月3日在线发表在《癌细胞》杂志上。

据研究人员介绍，T_H2细胞和先天性淋巴细胞2（ILC2）可以通过分泌促肿瘤细胞因子如白细胞介素-4（IL-4）、IL-5和IL-13刺激肿瘤生长。然而，2型免疫细胞运输到肿瘤微环境的机制尚不清楚。

研究人员发现，致癌性Kras^G12D增加了胰腺导管腺癌（PDAC）细胞中IL-33的表达，它招募并激活了T_H2和ILC2细胞。相应地，癌细胞特异性敲除IL-33会减少T_H2和ILC2的招募，并促进肿瘤的消退。出乎意料的是，IL-33的分泌依赖于瘤内真菌生物群。IL-33的基因缺失或抗真菌治疗会减少T_H2和ILC2的浸润并增加生存率。一致的是，在大约20%的人类PDAC中观察到IL-33的高表达，并且表达主要限制在癌细胞中。这些数据扩展了人们对驱动PDAC肿瘤进展机制的认识，并确定了瘤内真菌组驱动IL-33分泌的可治疗靶向途径。

附：英文原文

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

Author: Aftab Alam, Eric Levanduski, Parker Denz, Helena Solleiro Villavicencio, Maulasri Bhatta, Lamees Alhorebi, Yali Zhang, Eduardo Cortes Gomez, Brian Morreale, Sharon Senchanthisai, Jun Li, Steven G. Turowski, Sandra Sexton, Sheila Jani Sait, Prashant K. Singh, Jianmin Wang, Anirban Maitra, Pawel Kalinski, Ronald A. DePinho, Huamin Wang, Wenting Liao, Scott I. Abrams, Brahm H. Segal, Prasenjit Dey

Issue&Volume: 2022-02-03

Abstract: TH2 cells and innate lymphoid cells 2 (ILC2) can stimulate tumor growth by secretingpro-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 microenvironmentare unknown. Here, we show that oncogenic KrasG12D increases IL-33 expression in pancreatic ductal adenocarcinoma (PDAC) cells, whichrecruits and activates TH2 and ILC2 cells. Correspondingly, cancer-cell-specific deletion of IL-33 reducesTH2 and ILC2 recruitment and promotes tumor regression. Unexpectedly, IL-33 secretionis dependent on the intratumoral fungal mycobiome. Genetic deletion of IL-33 or anti-fungaltreatment decreases TH2 and ILC2 infiltration and increases survival. Consistently, high IL-33 expressionis observed in approximately 20% of human PDAC, and expression is mainly restrictedto cancer cells. These data expand our knowledge of the mechanisms driving PDAC tumorprogression and identify therapeutically targetable pathways involving intratumoralmycobiome-driven secretion of IL-33.

DOI: 10.1016/j.ccell.2022.01.003

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00005-8