Nicotine exhausts CD8+ T cells against tumor cells through increasing miR-629-5p to repress IL2RB-mediated granzyme B expression

Chun Chia Cheng, Hsin Chi Lin, Ya Wen Chiang, Jungshan Chang, Zong Lin Sie, Bi Ling Yang, Ken Hong Lim, Cheng Liang Peng, Ai Sheng Ho, Yi Fang Chang

Research output: Contribution to journalArticlepeer-review

Abstract

The mechanism exhausting CD8+ T cells is not completely clear against tumors. Literature has demonstrated that cigarette smoking disables the immunological activity, so we propose nicotine is able to exhaust CD8+ T cells. The CD8+ T cells from healthy volunteers with and without cigarette smoking and the capacity of CD8+ T cells against tumor cells were investigated. RNAseq was used to investigate the gene profiling expression in CD8+ T cells. Meanwhile, small RNAseq was also used to search novel microRNAs involved in the exhaustion of CD8+ T cells. The effect of nicotine exhausting CD8+ T cells was investigated in vitro and in the humanized tumor xenografts in vivo. We found that CD8+ T cells were able to reduce cell viability in lung cancer HCC827 and A549 cells, that secreted granzyme B, but CD8+ T cells from the healthy cigarette smokers lost anti-HCC827 effect. Moreover, nicotine suppressed the anti-HCC827 effect of CD8+ T cells. RNAseq revealed lower levels of IL2RB and GZMB in the exhausted CD8+ T cells. We identified that miR-629-5p was increased by nicotine, that targeted IL2RB. Transfection of miR-629-5p mimic reduced IL2RB and GZMB levels. We further validated that nicotine reduced granzyme B levels using a nuclear imaging technique, and demonstrated that nicotine exhausted peripheral blood mononuclear cells against HCC827 growth in the humanized tumor xenografts. This study demonstrated that nicotine exhausted CD8+ T cells against HCC827 cells through increasing miR-629-5p to suppress IL2RB.

Original languageEnglish
Pages (from-to)1351-1364
Number of pages14
JournalCancer Immunology, Immunotherapy
Volume70
Issue number5
DOIs
Publication statusPublished - May 2021

Keywords

  • CD8 T cells
  • Granzyme B
  • IL2RB
  • Nicotine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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