Epstein-Barr Virus (EBV)+ Post-Transplant Lymphoproliferative Disorder (PTLD) is Associated with Tumor CCL3/CCL4 Expression and an Increase in Tumor-Infiltrating Monocytes
J. Toh1, F. Vallania1, W. A. Haynes1, G. Bhagat2, F. E. Craig3, S. H. Swerdlow4, T. Tousseyn5, S. M. Krams1, P. Khatri1, O. M. Martinez1
1Stanford University School of Medicine, Stanford, CA, 2Columbia University Medical Center, New York City, NY, 3Mayo Clinic College of Medicine, Phoenix, AZ, 4University of Pittsburgh School of Medicine, Pittsburgh, PA, 5Katholieke Universiteit Leuven, Leuven, Belgium
Meeting: 2020 American Transplant Congress
Abstract number: C-211
Keywords: Epstein-Barr virus (EBV), Meta-analysis, Mononuclear leukocytes, Post-transplant lymphoproliferative disorder (PTLD)
Session Name: Poster Session C: PTLD/Malignancies: All Topics
Session Type: Poster Session
Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: PTLD is a serious post-transplant complication that encompasses a spectrum of abnormal lymphoproliferations, including B cell lymphoma-type PTLDs. Although many are EBV-driven, a significant minority are not. EBV employs diverse immune evasion strategies and EBV+ lymphoma-type PTLDs also exhibit immunomodulatory phenotypes. To better characterize the interactions between EBV and host immunity in PTLD, we used systems biology approaches on EBV+ and EBV- PTLD tumor samples to identify immune cell types and host genes associated with EBV-driven oncogenesis.
*Methods: Using three B cell lymphoma-type PTLD gene expression datasets with EBV+ and EBV- samples (n = 60, monomorphic and polymorphic PTLD), we performed in silico deconvolution with our immunoStates basis matrix and support vector regression to identify consistently enriched/deficient immune cell types in EBV+ PTLDs. An integrated multi-cohort analysis on these datasets also identified differentially expressed genes in EBV+ PTLD. In addition, we investigated the expression of several genes of interest in EBV+ B cell spontaneous lymphoblastoid cell lines (SLCL) derived from an independent cohort of patients with EBV+ PTLD and compared them with EBV- diffuse large B cell lymphoma (DLBCL) cell lines.
*Results: Our deconvolution analysis found that monocytes are enriched in EBV+ compared to EBV- PTLD . EBV+ PTLD tumors have increased transcript levels of CCL3, CCL3L1, CCL3L3, and CCL4, which encode cytokines known to be chemotactic for monocytes. We further validated the upregulation of these genes in EBV+ SLCL relative to EBV- DLBCL cell lines, both at the transcript level (CCL3, CCL3L1, CCL3L3, CCL4) via RT-qPCR, and at the protein level (CCL3, CCL4) via ELISA.
*Conclusions: Our results indicate that EBV influences interactions between the neoplastic cells and the host immune system in EBV+ PTLD. Specifically, monocytes and monocyte-attracting chemokines are enriched in the EBV+ PTLD microenvironment, and EBV+ B lymphoma cell lines derived from patients with PTLD secrete these chemokines. Thus, monocytes may play a role in the pathogenesis of EBV+ B cell lymphomas where host immunity is compromised.
To cite this abstract in AMA style:Toh J, Vallania F, Haynes WA, Bhagat G, Craig FE, Swerdlow SH, Tousseyn T, Krams SM, Khatri P, Martinez OM. Epstein-Barr Virus (EBV)+ Post-Transplant Lymphoproliferative Disorder (PTLD) is Associated with Tumor CCL3/CCL4 Expression and an Increase in Tumor-Infiltrating Monocytes [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/epstein-barr-virus-ebv-post-transplant-lymphoproliferative-disorder-ptld-is-associated-with-tumor-ccl3-ccl4-expression-and-an-increase-in-tumor-infiltrating-monocytes/. Accessed March 26, 2023.
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