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Poster display session

3859 - Post-transcriptional regulation of immune checkpoint genes by mir-16 in melanoma

Date

10 Sep 2017

Session

Poster display session

Presenters

Raya Leibowitz-Amit

Citation

Annals of Oncology (2017) 28 (suppl_5): v428-v448. 10.1093/annonc/mdx377

Authors

R. Leibowitz-Amit1, A. Layani2, J. Roszik3, Y. Sidi2, D. Avni2, E. Grimm4

Author affiliations

  • 1 Oncology, Chaim Sheba Medical Center, 52621 - Ramat Gan/IL
  • 2 Cancer Research Center, Chaim Sheba Medical Center, 52621 - Ramat Gan/IL
  • 3 Genomic Medicine, MD Anderson Cancer center, 77030 - Houston/US
  • 4 Melanoma Medical Oncology, MD Anderson Cancer center, 77030 - Houston/US
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Resources

Abstract 3859

Background

The complex interface between T lymphocytes and cancer ('the immunological synapse') comprises of both co-stimulatory and co-inhibitory proteins that modulate lymphocytes towards activation or anergy. 'Checkpoint inhibitors' have impressive activity in melanoma, but not all patients respond and drug resistance often develops. MiRNAs are master regulators of gene expression. Our aim is to study the regulation of the immunological synapse by miRNAs in melanoma.

Methods

Bioinformatic analyses of mRNAs and miRNA expression in 451 samples from the melanoma TCGA database was performed. Spearman rho correlation coefficients were calculated and survival analysis was performed using the Kaplan-Meier method. Direct mRNA targets of miRNAs were found using luciferase reporter assays, and mRNA/miRNA expression was assessed by qRT-PCR following either ectopic expression or depletion of specific miRNAs.

Results

Of 15 checkpoint mRNAs and 8 miRNAs examined, nine checkpoint mRNAs showed a highly statistically significant positive correlation to each other and, to a lesser extent, to mir-16. These results were fully corroborated in vitro. Mir-16 may potentially target the 3'UTR of 3 of these mRNAs. CD80 (B7.1) was found to a direct target of mir16 in vitro. Overexpression of mir-16 in melanoma cell lines led to downregulation of CD80, CD274 (PD-L1) and CD40, while downregulation of mir-16 increased the expression of these genes. Survival data from 163 stage III melanoma patients show that high levels of mir-16 and low levels of any of six checkpoint mRNAs (among them CD80) is significantly associated with poor prognosis.

Conclusions

Our results suggest that mir-16 and many checkpoint mRNAs are generally under a strict joint transcriptional regulation. The ability of mir-16 to decrease CD80 expression suggests that it serves as a key regulator of the immunological sample. We hypothesize that in vivo, an aberrantly high expression of mir-16 decreases the expression of the co-stimulatory checkpoint CD80 in melanoma and other checkpoint mRNAs, leading to immune evasion and compromised outcome. Further elucidation of both the transcriptional and post-transcriptional regulation of the immunological synapse may help point to novel targets and means for immune modulation.

Clinical trial identification

Legal entity responsible for the study

Raya Leibowitz-Amit

Funding

Israeli Scientific Foundation (ISF)

Disclosure

All authors have declared no conflicts of interest.

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