Graft-versus-host disease prophylaxis shapes T cell biology and immune reconstitution after hematopoietic cell transplant
Year: 2026
Type: article
Abstract: Successful hematopoietic cell transplant requires immunosuppression to prevent graft-versus-host disease (GVHD), a lethal, T cell-mediated complication. The phase 3 BMT CTN 1703 trial demonstrated superior GVHD-free/relapse-free survival for posttransplant cyclophosphamide (PT-Cy)-based GVHD prophylaxis versus tacrolimus/methotrexate (Tac/MTX), but the T cell biology underpinning these outcomes remains unknown. To determine this, 324 patients were coenrolled onto BMT CTN 1801 to investigate the distinct T cell immune reconstitution pathways of these regimens, including extensive evaluation of T cell receptor (TCR) repertoire, via sequencing of 2359 longitudinal samples and 180,432,350 T cells. Multimodal T cell analysis revealed that PT-Cy was associated with pan-T cell deletion followed by delayed T cell expansion from a smaller founder population compared with Tac/MTX. This created a T cell diversity bottleneck, leading to reduced TCR repertoire diversity for 2 years posttransplant. Reduced TCR diversity, more common in patients receiving PT-Cy, was linked to protection against chronic GVHD when patients were analyzed without regard to study arm. Leveraging donor- and host-specific TCR clonal analysis, we determined that PT-Cy-mediated T cell depletion also depleted pathogen-specific TCRs, rendering PT-Cy patients more likely to lack detectable graft-derived pathogen-specific TCRs early after transplant, which was associated with an increased risk of severe infection. This study reveals how distinct immunosuppression strategies uniquely remodel T cell immunity and shape divergent transplant outcomes.
Source: Science Translational Medicine
Authors: Susan DeWolf, Steven J. Siegel, Joseph Schmalz, Wael Saber, Alexandre Albanese, Jiayi Dong, Michael J. Martens, Brent Logan, Lorenzo Iovino, Kayleigh Ingersoll-Ohmdahl, Nicholas Winn, Edward Chen, James Kaminski, Donna Neuberg, Kyle Hebert, Paula Keskula, Jillian Zavistaski, Lea Steinberg, Isabella Schichter, Zoe Katsamakis, Lorenzo Cagnin, Vanessa Hernandez, Makya Warren, Kristy Applegate, Merav Bar, Saurabh Chhabra, Sung Won Choi, William Clark, Suman Das, Robert Jenq, Richard J. Jones, John E. Levine, Hemant Murthy, Armin Rashidi, Marcie Riches, Karamjeet Sandhu, Anthony D. Sung, Karilyn Larkin, Monzr M. Al Malki, Mahasweta Gooptu, Hany Elmariah, Amin Alousi, Lyndsey Runaas, Brian Shaffer, Andrew Rezvani, Najla El Jurdi, Alison W. Loren, Danielle Scheffey, Catherine Sanders, Mehdi Hamadani, Jarrod A. Dudakov, Stephanie Bien, Harlan Robins, Mary Horowitz, Javier Bolaños-Meade, Shernan Holtan, Ami S. Bhatt, Miguel-Angel Perales, Leslie S. Kean
Institutions: Memorial Sloan Kettering Cancer Center, Boston Children's Hospital, Harvard University, Adaptive Biotechnologies (United States), Medical College of Wisconsin, Fred Hutch Cancer Center, Broad Institute, Massachusetts Institute of Technology, Dana-Farber Cancer Institute, Emmes (United States), Mayo Clinic Hospital, University of Michigan, Virginia Commonwealth University, Vanderbilt University, City Of Hope National Medical Center, City of Hope, Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Mayo Clinic, Mayo Clinic in Florida, Mayo Clinic Comprehensive Cancer Center (Florida), The University of Kansas Health System, University of Kansas Medical Center, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Moffitt Cancer Center, The University of Texas MD Anderson Cancer Center, Weill Cornell Medicine, Stanford Medicine, Stanford University, National Institutes of Health, University of Minnesota, National Cancer Institute, Center for Cancer Research, University of Pennsylvania, University of Washington, Roswell Park Comprehensive Cancer Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Blood & Marrow Transplant Clinical Trials Network Data Coordinating Center, Prognostic implications of mitochondrial inheritance in myelodysplastic syndromes after stem-cell transplantation, BMT CTN Core - University of Minnesota, Mechanisms and Therapy of Chronic Graft-vs.-Host Disease, Optimizing HCT Outcomes: A Multi-omic Investigation, BMT Core - Johns Hopkins, Novel Biologic Therapies for GVHD, Blood and Marrow Transplant Clinical Trials Network (BMT CTN) - Core Clinical Centers - UG1, Blood and Marrow Transplant Clinical Trials Network DCC- The Medical College of Wisconsin, Inc., BMT Core - MSK
OpenAlex ID: W7223154345