title: Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression.
abstract: 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.
authors.forename: Regina
authors.initials: R
authors.lastname: Lin
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Chunyan
authors.initials: C
authors.lastname: Hu
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Jose
authors.initials: J
authors.lastname: Sevilla
authors.forename: Ying
authors.initials: Y
authors.lastname: Wan
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: Bo
authors.initials: B
authors.lastname: Zhu
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D005260:Female; D053804:Granzymes / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007111:Immunity, Cellular; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology
chemical_list: C552430:MIRN23a microRNA, human; D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse; C513258:Prdm1 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse