title: The tumor microenvironment disarms CD8+T lymphocyte function via a miR-26a-EZH2 axis.
abstract: One of the most important factors that limit the potency of CD8+cytotoxic T lymphocyte (CTL) responses is the tumor microenvironment (TME). Here, we provide evidence that miR-26a is a negative regulator of CTL function in the TME. Specifically, we identified miR-26a as a crucial suppressor gene in CTLs from the TME, as we found that, miR-26a expression was elevated in CTLs to respond to TME secretome stimulation. CTLs from miR-26a-transgenic mice showed impaired IFNγ and granzyme B production in response to their cognate antigen. Conversely, we found that miR-26a inhibition in CTLs could effectively increase the cytotoxicity and suppress tumor growth. Mechanically, we identified EZH2 as a direct target of miR-26a. miR-26a and EZH2 expression were found to be inversely correlated in CTLs, and the inhibition of EZH2 in CTLs impairs CTL function. These functional correlations were validated in a cohort of non-small cell lung cancer patients, indicating that the miR-26a-EZH2 axis is clinically relevant. Our findings suggested that miR-26a silencing as a novel strategy to improve the efficacy of CTL-based cancer immunotherapy.
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Department of Immunology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Haixia
authors.initials: H
authors.lastname: Long
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Department of Immunology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Xiang
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University , Chongqing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Luo
authors.affiliation: Biomedical Analysis Center, Third Military Medical University , Chongqing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Immunology, Duke University Medical Center , Durham, NC, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Lin
authors.affiliation: Department of Immunology, Duke University Medical Center , Durham, NC, USA.
authors.forename: Siqi
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Immunology, Duke University Medical Center , Durham, NC, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University , Chongqing, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Hu
authors.affiliation: Biomedical Analysis Center, Third Military Medical University , Chongqing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Immunology, Duke University Medical Center , Durham, NC, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wong
authors.affiliation: Biomedical Analysis Center, Third Military Medical University , Chongqing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Immunology, Duke University Medical Center , Durham, NC, USA.
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
authors.affiliation: Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of tumor immunotherapy, Chongqing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhu
keywords: Cytotoxic T lymphocyte; EZH2; miR-26a; tumor microenvironment; tumor-infiltrating T lymphocytes