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Nat Immunol. 2018 Oct;19(10):1112-1125. doi: 10.1038/s41590-018-0207-y. Epub 2018 Sep 17.

NKILA lncRNA promotes tumor immune evasion by sensitizing T cells to activation-induced cell death.

Huang D1,2, Chen J1,2, Yang L1,2, Ouyang Q1,2, Li J1,2, Lao L1,2, Zhao J1,2, Liu J1,2, Lu Y1,2, Xing Y1,2, Chen F1,2, Su F1,2, Yao H3, Liu Q1,2, Su S4,5, Song E6,7,8.

Author information

1
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
2
Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
3
Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
4
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. sushch@mail.sysu.edu.cn.
5
Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. sushch@mail.sysu.edu.cn.
6
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. songew@mail.sysu.edu.cn.
7
Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. songew@mail.sysu.edu.cn.
8
Program in Molecular Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. songew@mail.sysu.edu.cn.

Abstract

Activation-induced cell death (AICD) of T lymphocytes can be exploited by cancers to escape immunological destruction. We demonstrated that tumor-specific cytotoxic T lymphocytes (CTLs) and type 1 helper T (TH1) cells, rather than type 2 helper T cells and regulatory T cells, were sensitive to AICD in breast and lung cancer microenvironments. NKILA, an NF-κB-interacting long noncoding RNA (lncRNA), regulates T cell sensitivity to AICD by inhibiting NF-κB activity. Mechanistically, calcium influx in stimulated T cells via T cell-receptor signaling activates calmodulin, thereby removing deacetylase from the NKILA promoter and enhancing STAT1-mediated transcription. Administering CTLs with NKILA knockdown effectively inhibited growth of breast cancer patient-derived xenografts in mice by increasing CTL infiltration. Clinically, NKILA overexpression in tumor-specific CTLs and TH1 cells correlated with their apoptosis and shorter patient survival. Our findings underscore the importance of lncRNAs in determining tumor-mediated T cell AICD and suggest that engineering lncRNAs in adoptively transferred T cells might provide a novel antitumor immunotherapy.

PMID:
30224822
DOI:
10.1038/s41590-018-0207-y
[Indexed for MEDLINE]

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