Volume 30, No 7, Jul 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 7, July 2020: 610-622

ORIGINAL ARTICLES

Transdifferentiation of tumor infiltrating innate lymphoid cells during progression of colorectal cancer

Shuo Wang^1,2,3,†,* , Yuan Qu^1,4,† , Pengyan Xia^1,5,† , Yi Chen^1,6,† , Xiaoxiao Zhu⁷ , Jing Zhang⁸ , Guan Wang⁸ , Yong Tian^7,* , Jianming Ying^8,†,* , Zusen Fan^1,4

¹CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China;
²CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China;
³Center for Biosafety MegaScience, Chinese Academy of Sciences, Wuhan, 430071 Hubei, China;
⁴University of Chinese Academy of Sciences, 100049 Beijing, China;
⁵Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, 100871 Beijing, China;
⁶Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China;
⁷CAS Key Laboratory of RNA Biology; Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China
⁸Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021 Beijing, China
^†These authors contributed equally
Correspondence: Shuo Wang(wangshuo@im.ac.cn)Yong Tian(tiany@ibp.ac.cn)Jianming Ying(jmying@cicams.ac.cn)

Innate lymphoid cells (ILCs) reside in mucosal surfaces to potentiate immune responses, sustain mucosal integrity and maintain tissue homeostasis. However, how tumor infiltrating ILCs modulate tumor development and progression is unclear. Here we profiled tumor infiltrating ILCs during colorectal cancer (CRC) progression by single-cell RNA sequencing. We identified six clusters of tumor infiltrating ILCs with unique features. ILC1s expressed inhibitory receptors and underwent inhibitory functional conversion at the late stage of CRC. ILC2s were classified into three subsets (called ILC2-A, -B, -C), of which ILC2-C subset could facilitate tumor progression. HS3ST1 and PD1 were highly expressed in ILC2s of late stage CRC tumors and deficiency of HS3ST1 or PD1 in ILC2s suppressed tumor growth. Moreover, ILC3s transdifferentiated into ILCregs during CRC progression and ILCregs promoted tumor growth. Of note, TGF-β signaling initiated the conversion of ILC3s to ILCregs and blockade of TGF-β signaling could disrupt the ILCreg transdifferentiation and inhibited tumor growth. Thus, intervention of ILC conversions might be a potential strategy for CRC immunotherapy.

https://doi.org/10.1038/s41422-020-0312-y

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