EBV+ PTLD Tumor MicroRNAs Detected in Circulating Extracellular Vesicles Are Decreased in Pediatric Transplant Recipients with EBV+ PTLD

A. Sen¹, J. Enriquez¹, M. Rao¹, M. Glass¹, Y. Balachandran¹, S. Syed¹, C. Twist¹, K. Weinberg¹, S. D. Boyd¹, D. Bernstein¹, A. Trickey¹, D. Gratzinger¹, B. Tan¹, M. G. Lapasaran¹, M. A. Robien², M. Brown³, B. Armstrong⁴, M. Sever⁴, D. Desai⁵, G. Mazariegos⁶, C. Chin⁷, T. Fishbein⁸, R. S. Venick⁹, A. Tekin¹⁰, H. Zimmermann¹¹, R. U. Trappe¹², C. O. Esquivel¹, O. M. Martinez¹, S. M. Krams¹

¹Stanford U, Palo Alto, CA, ²NIH, Bethesda, MD, ³NIAID, Bethesda, MD, ⁴Rho, Durham, NC, ⁵UT Southwestern, Dallas, TX, ⁶Pittsburgh U, Pittsburgh, PA, ⁷CCHMC, Cincinnati, OH, ⁸Georgetown U, Washington, DC, ⁹UCLA, LA, CA, ¹⁰Miami U, Miami, FL, ¹¹DIAKO Ev. Diakonie-Krankenhaus, Bremen, Germany, ¹²Charité - Universitätsmedizin, Berlin, Germany

Meeting: 2022 American Transplant Congress

Abstract number: 62

Keywords: Epstein-Barr virus (EBV), Post-transplant lymphoproliferative disorder (PTLD), Reverse transcriptase PCR

Topic: Clinical Science » Infection Disease » 28 - PTLD: All Topics

Session Information

Session Name: PTLD and Malignancies

Session Type: Rapid Fire Oral Abstract

Date: Sunday, June 5, 2022

Session Time: 3:30pm-5:00pm

Presentation Time: 4:00pm-4:10pm

Location: Hynes Room 309

*Purpose: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation. Predisposing factors for PTLD include primary Epstein-Barr virus (EBV) infection in children, reactivation of EBV in recipient B cells, and decreased T cell immunity due to immunosuppression. Previously, we demonstrated that EBV infection markedly reshapes the microRNA (miR) landscape in EBV+ B cell lines leading to increased production of IL-10.

*Methods: To establish the miRNAome of PTLD tumors we analyzed archived FFPE shavings of tumor tissues from solid organ transplant (SOT) recipients with EBV+ PTLD (n=14) and EBV- PTLD (n=10), by miR microarray analysis and quantitative PCR. Blood was obtained from pediatric SOT recipients enrolled at seven sites in the NIAID-sponsored Clinical Trials of Organ Transplantation in Children (CTOTC)-06, a prospective multi-institutional study intended to identify viral and immune biomarkers of EBV-associated PTLD.

*Results: The miRNAome of the EBV+ PTLD tumors strikingly differs from the EBV- PTLD tumors. Tumor levels of miRs-17, 19, 106a, and 194 were reduced in the EBV+ PTLD tumors with miR-194 (p<0.01) being significantly reduced compared to EBV- controls. We next quantitated levels of miRs-17, 19, 106a, 155, and 194 in the plasma and extracellular vesicles (EV; 50-70 nm as determined by nanoparticle tracking analysis) from EBV+ PTLD+ SOT recipients (n=18) and matched EBV+ PTLD- controls (n=37). Plasma and EV levels of miRs-17, 19, 106a, and 194 were reduced in the EBV+ PTLD+ group compared to matched controls, with miRs-17 (p=0.034; plasma), miRs-19 (p=0.029; EV) and miR 106a (p=0.007; plasma and EV) being significantly reduced. Similar levels of miR-155 were detected in the plasma and EV of all pediatric SOT recipients. Importantly, ~90% of the cell-free miRs were contained within the EV.

*Conclusions: This confirms that EBV+ PTLD tumor miRs are detected in the circulation; tumor-derived EVs may have the potential to target and regulate cells of the immune system. Further development of diagnostic, mechanistic, and potential therapeutic uses of these miRNA in PTLD is warranted.

To cite this abstract in AMA style:

Sen A, Enriquez J, Rao M, Glass M, Balachandran Y, Syed S, Twist C, Weinberg K, Boyd SD, Bernstein D, Trickey A, Gratzinger D, Tan B, Lapasaran MG, Robien MA, Brown M, Armstrong B, Sever M, Desai D, Mazariegos G, Chin C, Fishbein T, Venick RS, Tekin A, Zimmermann H, Trappe RU, Esquivel CO, Martinez OM, Krams SM. EBV+ PTLD Tumor MicroRNAs Detected in Circulating Extracellular Vesicles Are Decreased in Pediatric Transplant Recipients with EBV+ PTLD [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/ebv-ptld-tumor-micrornas-detected-in-circulating-extracellular-vesicles-are-decreased-in-pediatric-transplant-recipients-with-ebv-ptld/. Accessed January 18, 2025.

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