title: MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints.
abstract: Antibody therapeutic targeting of the immune checkpoints cytotoxic T-lymphocyte-associated molecule 4 (CTLA-4) and programmed cell death 1 (PD-1) has demonstrated marked tumor regression in clinical trials. MicroRNAs (miRNAs) can modulate multiple gene transcripts including possibly more than one immune checkpoint and could be exploited as immune therapeutics.
  
  
  
  Using online miRNA targeting prediction algorithms, we searched for miRNAs that were predicted to target both PD-1 and CTLA-4. MiR-138 emerged as a leading candidate. The effects of miR-138 on CTLA-4 and PD-1 expression and function in T cells were determined and the therapeutic effect of intravenous administration of miR-138 was investigated in both immune-competent and -incompetent murine models of GL261 glioma.
  
  
  
  Target binding algorithms predicted that miR-138 could bind the 3' untranslated regions of CTLA-4 and PD-1, which was confirmed with luciferase expression assays. Transfection of human CD4+ T cells with miR-138 suppressed expression of CTLA-4, PD-1, and Forkhead box protein 3 (FoxP3) in transfected human CD4+ T cells. In vivo miR-138 treatment of GL261 gliomas in immune-competent mice demonstrated marked tumor regression, a 43% increase in median survival time (P = .011), and an associated decrease in intratumoral FoxP3+ regulatory T cells, CTLA-4, and PD-1 expression. This treatment effect was lost in nude immune-incompetent mice and with depletion of CD4+ or CD8+ T cells, and miR-138 had no suppressive effect on glioma cells when treated directly at physiological in vivo doses.
  
  
  
  MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints which may have rapid translational potential as a novel immunotherapeutic agent.
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Edjah K
authors.initials: EK
authors.lastname: Nduom
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Ling-Yuan
authors.initials: LY
authors.lastname: Kong
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Yuuri
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Shuo
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Konrad
authors.initials: K
authors.lastname: Gabrusiewicz
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Ling
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Neal
authors.initials: N
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Wei
authors.initials: W
authors.lastname: Qiao
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Shouhao
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Greg N
authors.initials: GN
authors.lastname: Fuller
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gilbert
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Willem
authors.initials: W
authors.lastname: Overwijk
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (J.W., E.K.N., L.-Y.K., Y.H., S.X., K.G., X.L., N.H., A.B.H.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.Q., S.Z.); Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.I.); Departments of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Departments of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (W.O.); Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.A.C.); Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (S.X.).
authors.forename: Amy B
authors.initials: AB
authors.lastname: Heimberger
mesh_terms: D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005910:Glioma / Q000276:immunology / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D035683:MicroRNAs / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C546110:MIRN138 microRNA, human; D035683:MicroRNAs; D061026:Programmed Cell Death 1 Receptor
keywords: CTLA-4; PD-1; glioblastoma; miR-138; microRNAs