IT-22 * TARGETING THE IMMUNE CHECKPOINT NETWORK WITH miR-138 EXERTS THERAPEUTIC EFFICACY IN MURINE MODELS OF GLIOMA
Year: 2014
Type: conference-abstract
Abstract: Antibody therapeutic targeting of the immune checkpoints CTLA-4 and PD-1 has demonstrated marked tumor regression in clinical trials; however, this requires multimodality treatment and has known toxicity. MicroRNAs (miRNAs) can modulate gene transcripts, including those of tumor-mediated immune suppressive pathways. MiRNAs can be delivered to the systemic immune compartment, which can initiate anti-tumor immune response, overcoming the issue of miRNA delivery to the tumor. To identify potential miRNA therapeutics, we exploited human glioblastoma miRNA expression assays followed by a screening process of predicted binding sites in the 3' UTR of immune suppressive pathways and immune checkpoints. MiR-138 emerged as a leading candidate with binding sites in the 3' UTR of CTLA-4 and PD-1, which were functionally confirmed with luciferase expression assays. The miR-138 targeting of CTLA-4 and PD-1 was further validated by expression analysis of transfected human CD4+ T cells. Using human glioma tumor microarrays and in situ hybridization, heterogeneous expression of miR-138 was found amongst all glioma grades and pathological subtypes. The PD-1 ligand, PD-L1, was frequently expressed in glioblastomas based on immunohistochemistry and ex vivo flow cytometry from human glioblastoma. Analysis of TCGA database revealed that co-expression of PD-1 and PD-L1 impacts glioblastoma survival. The role of CTLA-4 in glioblastoma-mediated immune suppression is well documented, suggesting that targeting of CTLA-4 and PD-1 with miR-138 in glioblastoma patients may have anti-tumor activity. In vivo treatment with miR-138 in immune-competent mice with GL261 gliomas demonstrated marked tumor regression, a 43% increase in median survival (P = 0.011), and an associated decrease in intratumoral FoxP3+ Tregs, CTLA-4, and PD-1 expression. Conversely, in an immune-incompetent animal background, miR-138 failed to exert any therapeutic effect, indicating that miR-138 mediates in vivo activity via the immune system. Cumulatively, our data indicate that miR-138 may be an active and novel immunotherapeutic agent for human glioblastoma patients.
Source: Neuro-Oncology
Authors: E. K. Nduom, J. Wei, L.-Y. Kong, S. Xu, K. Gabrusiewicz, X. Ling, N. Huang, W. Qiao, S. Zhou, C. Ivan, J. Q. Chen, Y. Ji, L. Radvanyi, G. N. Fuller, M. Gilbert, C. A. Conrad, W. Overwijk, G. A. Calin, A. B. Heimberger
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2132496653