Browsing by Author "Choi, Sung W."

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    Graft-Versus-Host Disease-Free Antitumoral Signature After Allogeneic Donor Lymphocyte Injection Identified by Proteomics and Systems Biology
    (American Society of Clinical Oncology, 2019) Liu, Xiaowen; Yue, Zongliang; Cao, Yimou; Taylor, Lauren; Zhang, Qing; Choi, Sung W.; Hanash, Samir; Ito, Sawa; Chen, Jake Yue; Wu, Huanmei; Paczesny, Sophie; Pediatrics, School of Medicine
    PURPOSE: As a tumor immunotherapy, allogeneic hematopoietic cell transplantation with subsequent donor lymphocyte injection (DLI) aims to induce the graft-versus-tumor (GVT) effect but often also leads to acute graft-versus-host disease (GVHD). Plasma tests that can predict the likelihood of GVT without GVHD are still needed. PATIENTS AND METHODS: We first used an intact-protein analysis system to profile the plasma proteome post-DLI of patients who experienced GVT and acute GVHD for comparison with the proteome of patients who experienced GVT without GVHD in a training set. Our novel six-step systems biology analysis involved removing common proteins and GVHD-specific proteins, creating a protein-protein interaction network, calculating relevance and penalty scores, and visualizing candidate biomarkers in gene networks. We then performed a second proteomics experiment in a validation set of patients who experienced GVT without acute GVHD after DLI for comparison with the proteome of patients before DLI. We next combined the two experiments to define a biologically relevant signature of GVT without GVHD. An independent experiment with single-cell profiling in tumor antigen-activated T cells from a patient with post-hematopoietic cell transplantation relapse was performed. RESULTS: The approach provided a list of 46 proteins in the training set, and 30 proteins in the validation set were associated with GVT without GVHD. The combination of the two experiments defined a unique 61-protein signature of GVT without GVHD. Finally, the single-cell profiling in activated T cells found 43 of the 61 genes. Novel markers, such as RPL23, ILF2, CD58, and CRTAM, were identified and could be extended to other antitumoral responses. CONCLUSION: Our multiomic analysis provides, to our knowledge, the first human plasma signature for GVT without GVHD. Risk stratification on the basis of this signature would allow for customized treatment plans.
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    Prospective assessment of risk biomarkers of sinusoidal obstruction syndrome after hematopoietic cell transplantation
    (The American Society for Clinical Investigation, 2023-05-22) Han, Yan; Bidgoli, Alan; DePriest, Brittany P.; Méndez, Alejandra; Bijangi-Vishehsaraei, Khadijeh; Perez-Albuerne, Evelio D.; Krance, Robert A.; Renbarger, Jamie; Skiles, Jodi L.; Choi, Sung W.; Liu, Hao; Paczesny, Sophie; Biostatistics and Health Data Science, School of Medicine
    BACKGROUND: Currently, no laboratory tests exist to stratify for the risk of developing sinusoidal obstruction syndrome (SOS), an early endothelial complication after hematopoietic cell transplantation (HCT). Risk biomarkers of SOS have not been verified in a prospective cohort accounting for differences between practices across institutions. Herein, we aimed to define risk groups for SOS occurrence using 3 proteins: L-ficolin, hyaluronic acid (HA), and stimulation 2 (ST2). METHODS: Between 2017 and 2021, we prospectively accrued 80 pediatric patients across 4 US centers. Biomarkers were tested by ELISA blind to patient groupings and associated with SOS incidence on day 35 after HCT, and overall survival (OS) on day 100 after HCT. Cutpoints were identified using retrospective cohorts and applied to the prospective cohort. RESULTS: Combination of the 3 biomarkers measured on day 3 after HCT in the prospective cohort provided 80% (95% CI 55%–100%) sensitivity and 73% (95% CI 62%–83%) specificity for risk of SOS occurrence. Patients with low L-ficolin were 9 times (95% CI 3–32) more likely to develop SOS, while patients with high HA and ST2 were 6.5 (95% CI 1.9–22.0) and 5.5 (95% CI 2.3–13.1) times more likely to develop SOS. These 3 markers also predicted worse day 100 OS — L-ficolin: HR, 10.0 (95% CI 2.2–45.1), P = 0.0002; HA: HR, 4.1 (95% CI 1.0–16.4), P = 0.031; and ST2: HR, 3.9 (95% CI 0.9–16.4), P = 0.04. CONCLUSION: L-ficolin, HA, and ST2 levels measured as early as 3 days after HCT improved risk stratification for SOS occurrence and OS and may guide risk-adapted preemptive therapy.
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    Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease
    (American Society for Clinical Investigation, 2016-05-05) Li, Wei; Liu, Liangyi; Gomez, Aurelie; Zhang, Jilu; Ramadan, Abdulraouf; Zhang, Qing; Choi, Sung W.; Zhang, Peng; Greenson, Joel K.; Liu, Chen; Jiang, Di; Virts, Elizabeth; Kelich, Stephanie L.; Chu, Hong Wei; Flynn, Ryan; Blazar, Bruce R.; Hanenberg, Helmut; Hanash, Samir; Paczesny, Sophie; Department of Microbiology & Immunology, IU School of Medicine
    Gastrointestinal graft-versus-host-disease (GI-GVHD) is a life-threatening complication occurring after allogeneic hematopoietic cell transplantation (HCT), and a blood biomarker that permits stratification of HCT patients according to their risk of developing GI-GVHD would greatly aid treatment planning. Through in-depth, large-scale proteomic profiling of presymptomatic samples, we identified a T cell population expressing both CD146, a cell adhesion molecule, and CCR5, a chemokine receptor that is upregulated as early as 14 days after transplantation in patients who develop GI-GVHD. The CD4+CD146+CCR5+ T cell population is Th17 prone and increased by ICOS stimulation. shRNA knockdown of CD146 in T cells reduced their transmigration through endothelial cells, and maraviroc, a CCR5 inhibitor, reduced chemotaxis of the CD4+CD146+CCR5+ T cell population toward CCL14. Mice that received CD146 shRNA-transduced human T cells did not lose weight, showed better survival, and had fewer CD4+CD146+CCR5+ T cells and less pathogenic Th17 infiltration in the intestine, even compared with mice receiving maraviroc with control shRNA- transduced human T cells. Furthermore, the frequency of CD4+CD146+CCR5+ Tregs was increased in GI-GVHD patients, and these cells showed increased plasticity toward Th17 upon ICOS stimulation. Our findings can be applied to early risk stratification, as well as specific preventative therapeutic strategies following HCT.