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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology
  • Carcinoma / genetics
  • Carcinoma / immunology*
  • Carcinoma / pathology
  • Female
  • Heterografts
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / immunology*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Th1 Cells / immunology*
  • Tumor Escape / genetics*


  • RNA, Long Noncoding
  • long noncoding RNA NKILA, human