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Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression.

Publication ,  Journal Article
Lin, R; Chen, L; Chen, G; Hu, C; Jiang, S; Sevilla, J; Wan, Y; Sampson, JH; Zhu, B; Li, Q-J
Published in: J Clin Invest
December 2014

CD8(+) cytotoxic T lymphocytes (CTLs) have potent antitumor activity and therefore are leading candidates for use in tumor immunotherapy. The application of CTLs for clinical use has been limited by the susceptibility of ex vivo-expanded CTLs to become dysfunctional in response to immunosuppressive microenvironments. Here, we developed a microRNA-targeting (miRNA-targeting) approach that augments CTL cytotoxicity and preserves immunocompetence. Specifically, we screened for miRNAs that modulate cytotoxicity and identified miR-23a as a strong functional repressor of the transcription factor BLIMP-1, which promotes CTL cytotoxicity and effector cell differentiation. In a cohort of advanced lung cancer patients, miR-23a was upregulated in tumor-infiltrating CTLs, and expression correlated with impaired antitumor potential of patient CTLs. We determined that tumor-derived TGF-β directly suppresses CTL immune function by elevating miR-23a and downregulating BLIMP-1. Functional blocking of miR-23a in human CTLs enhanced granzyme B expression, and in mice with established tumors, immunotherapy with just a small number of tumor-specific CTLs in which miR-23a was inhibited robustly hindered tumor progression. Together, our findings provide a miRNA-based strategy that subverts the immunosuppression of CTLs that is often observed during adoptive cell transfer tumor immunotherapy and identify a TGF-β-mediated tumor immune-evasion pathway.

Duke Scholars

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

December 2014

Volume

124

Issue

12

Start / End Page

5352 / 5367

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta
  • Transcription Factors
  • Repressor Proteins
  • Positive Regulatory Domain I-Binding Factor 1
  • Neoplasms, Experimental
  • MicroRNAs
  • Mice
  • Male
  • Immunology
  • Immunity, Cellular
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lin, R., Chen, L., Chen, G., Hu, C., Jiang, S., Sevilla, J., … Li, Q.-J. (2014). Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression. J Clin Invest, 124(12), 5352–5367. https://doi.org/10.1172/JCI76561
Lin, Regina, Ling Chen, Gang Chen, Chunyan Hu, Shan Jiang, Jose Sevilla, Ying Wan, John H. Sampson, Bo Zhu, and Qi-Jing Li. “Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression.J Clin Invest 124, no. 12 (December 2014): 5352–67. https://doi.org/10.1172/JCI76561.
Lin R, Chen L, Chen G, Hu C, Jiang S, Sevilla J, et al. Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression. J Clin Invest. 2014 Dec;124(12):5352–67.
Lin, Regina, et al. “Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression.J Clin Invest, vol. 124, no. 12, Dec. 2014, pp. 5352–67. Pubmed, doi:10.1172/JCI76561.
Lin R, Chen L, Chen G, Hu C, Jiang S, Sevilla J, Wan Y, Sampson JH, Zhu B, Li Q-J. Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression. J Clin Invest. 2014 Dec;124(12):5352–5367.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

December 2014

Volume

124

Issue

12

Start / End Page

5352 / 5367

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta
  • Transcription Factors
  • Repressor Proteins
  • Positive Regulatory Domain I-Binding Factor 1
  • Neoplasms, Experimental
  • MicroRNAs
  • Mice
  • Male
  • Immunology
  • Immunity, Cellular