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MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints
Jun Wei1, Edjah K Nduom1, Ling-Yuan Kong1
1Department 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.).
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.
Insights
MicroRNA-138 (miR-138) targets immune checkpoints like CTLA-4 and PD-1, showing promise for glioma immunotherapy. This novel microRNA therapeutic significantly improved survival in mice by modulating T-cell responses.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immune checkpoint inhibitors targeting CTLA-4 and PD-1 have shown success in cancer treatment.
- MicroRNAs (miRNAs) offer a potential therapeutic strategy by modulating multiple gene targets, including immune checkpoints.
Purpose of the Study:
- To identify and evaluate microRNAs targeting both CTLA-4 and PD-1.
- To assess the therapeutic potential of miR-138 in a murine glioma model.
Main Methods:
- Bioinformatic prediction identified miR-138 as a potential miRNA targeting CTLA-4 and PD-1.
- Luciferase assays confirmed miR-138 binding to CTLA-4 and PD-1 3' UTRs.
- In vivo studies assessed miR-138 efficacy in immune-competent and -incompetent mice with GL261 gliomas.
Main Results:
- miR-138 transfection suppressed CTLA-4, PD-1, and FoxP3 expression in human T cells.
- Intravenous miR-138 administration in mice led to significant GL261 glioma regression and increased median survival by 43%.
- Treatment efficacy was dependent on T cells and reduced intratumoral immune checkpoint expression.
Conclusions:
- miR-138 demonstrates anti-glioma efficacy through immune checkpoint modulation.
- This microRNA has potential as a novel, rapidly translatable immunotherapeutic agent for cancer.
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