CXCR4-dependent migratory differences between peripheral Tregs and Tcons preserve GVL while limiting GVHD after HSCT
Year: 2026
Type: article
Abstract: ABSTRACT: Although studies on HLA-haploidentical hematopoietic stem cell transplant (HSCT) for high-risk acute myeloid leukemia (AML) showed that regulatory T-lymphocyte (Treg) and conventional T-lymphocyte (Tcon) immunotherapy prevents graft-versus-host disease (GVHD) while exerting T-cell-dependent graft-versus-leukemia (GVL) effect, its mechanism is not well known. The present study clarifies the mechanisms underlying this finding. In a xenogenic immunotherapy model, nonobese diabetic-scidIl2rgtm mice were engrafted with human primary AML and were treated with allogeneic human peripheral blood Tregs followed by Tcons. Treg/Tcon immunotherapy cleared leukemia without causing GVHD. Peripheral blood Tregs are largely CD45RO+ and express low levels of CXCR4 bone marrow (BM) homing receptor. They localized in peripheral tissues (ie, liver, gut), but not in the BM. Consequently, in the BM, Tcon effector function was not downregulated and indeed Tcons killed leukemic cells. In contrast, in peripheral tissues, Tcons showed no alloreactivity suggesting that their effector function had been downregulated by the Tregs. Thus, the GVL effect without GVHD was caused by the migratory features of peripheral blood Tregs. These data were confirmed in a major histocompatibility complex-mismatched BM transplant model using H-2b mice as recipients and H-2d mice as donors. Remarkably, in patients receiving T-cell-depleted haploidentical HSCT with Treg/Tcon immunotherapy, the infused Tregs were not found in the BM in the first month after transplant. In contrast, donor Tcons homed to the BM where they exerted leukemic-cell killing. In conclusion, to our knowledge, for the first time, we show the mechanism whereby immunotherapy with Tregs/Tcons prevents GVHD while preserving GVL in murine transplant models and in patients with leukemia who underwent transplantation.
Source: Blood Advances
Authors: Loredana Ruggeri, Antonio Pierini, Elena Urbani, Sara Ciardelli, Rachele Del Sordo, Rosaria Sola, Tiziana Zei, Roberta Iacucci Ostini, Simonetta Saldi, Francesco Maria Adamo, Antonella Mancusi, Karim Enrico Jardini, Eni Hoxha, Valerio Viglione, Rebecca Sembenico, Francesco Zorutti, Susanta Hui, Mauro Di Ianni, Franca Falzetti, Maria Paola Martelli, Cristina Mecucci, Cynthia Aristei, Alessandra Carotti, Massimo Fabrizio Martelli, Andrea Velardi
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
OpenAlex ID: W7203751505