MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints

Jun Wei, Edjah K. Nduom, Ling Yuan Kong, Yuuri Hashimoto, Shuo Xu, Konrad Gabrusiewicz, Xiaoyang Ling, Neal Huang, Wei Qiao, Shouhao Zhou, Cristina Ivan, Greg N. Fuller, Mark R. Gilbert, Willem Overwijk, George A. Calin, Amy B. Heimberger

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Background. 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. Methods. 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. Results. 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. Conclusions. MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints which may have rapid translational potential as a novel immunotherapeutic agent.

Original languageEnglish (US)
Pages (from-to)639-648
Number of pages10
JournalNeuro-oncology
Volume18
Issue number5
DOIs
StatePublished - May 1 2016

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Cytotoxic T-Lymphocytes
Glioma
Cell Death
MicroRNAs
Forkhead Transcription Factors
T-Lymphocytes
3' Untranslated Regions
Therapeutic Uses
Regulatory T-Lymphocytes
Therapeutics
Luciferases
Intravenous Administration
Transfection
Neoplasms
Clinical Trials
Survival
Antibodies
Genes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Wei, J., Nduom, E. K., Kong, L. Y., Hashimoto, Y., Xu, S., Gabrusiewicz, K., ... Heimberger, A. B. (2016). MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints. Neuro-oncology, 18(5), 639-648. https://doi.org/10.1093/neuonc/nov292
Wei, Jun ; Nduom, Edjah K. ; Kong, Ling Yuan ; Hashimoto, Yuuri ; Xu, Shuo ; Gabrusiewicz, Konrad ; Ling, Xiaoyang ; Huang, Neal ; Qiao, Wei ; Zhou, Shouhao ; Ivan, Cristina ; Fuller, Greg N. ; Gilbert, Mark R. ; Overwijk, Willem ; Calin, George A. ; Heimberger, Amy B. / MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints. In: Neuro-oncology. 2016 ; Vol. 18, No. 5. pp. 639-648.
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abstract = "Background. 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. Methods. 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. Results. 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. Conclusions. MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints which may have rapid translational potential as a novel immunotherapeutic agent.",
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Wei, J, Nduom, EK, Kong, LY, Hashimoto, Y, Xu, S, Gabrusiewicz, K, Ling, X, Huang, N, Qiao, W, Zhou, S, Ivan, C, Fuller, GN, Gilbert, MR, Overwijk, W, Calin, GA & Heimberger, AB 2016, 'MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints', Neuro-oncology, vol. 18, no. 5, pp. 639-648. https://doi.org/10.1093/neuonc/nov292

MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints. / Wei, Jun; Nduom, Edjah K.; Kong, Ling Yuan; Hashimoto, Yuuri; Xu, Shuo; Gabrusiewicz, Konrad; Ling, Xiaoyang; Huang, Neal; Qiao, Wei; Zhou, Shouhao; Ivan, Cristina; Fuller, Greg N.; Gilbert, Mark R.; Overwijk, Willem; Calin, George A.; Heimberger, Amy B.

In: Neuro-oncology, Vol. 18, No. 5, 01.05.2016, p. 639-648.

Research output: Contribution to journalArticle

TY - JOUR

T1 - MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints

AU - Wei, Jun

AU - Nduom, Edjah K.

AU - Kong, Ling Yuan

AU - Hashimoto, Yuuri

AU - Xu, Shuo

AU - Gabrusiewicz, Konrad

AU - Ling, Xiaoyang

AU - Huang, Neal

AU - Qiao, Wei

AU - Zhou, Shouhao

AU - Ivan, Cristina

AU - Fuller, Greg N.

AU - Gilbert, Mark R.

AU - Overwijk, Willem

AU - Calin, George A.

AU - Heimberger, Amy B.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Background. 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. Methods. 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. Results. 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. Conclusions. MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints which may have rapid translational potential as a novel immunotherapeutic agent.

AB - Background. 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. Methods. 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. Results. 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. Conclusions. MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints which may have rapid translational potential as a novel immunotherapeutic agent.

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Wei J, Nduom EK, Kong LY, Hashimoto Y, Xu S, Gabrusiewicz K et al. MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints. Neuro-oncology. 2016 May 1;18(5):639-648. https://doi.org/10.1093/neuonc/nov292