Development of a Protective Cellular Therapy to Prevent Graft Versus Host Disease Post Allogenic Hematopoietic Stem Cell Transplant 2331939

Abstract

Graft-versus-host disease (GVHD) remains a primary cause of morbidity and mortality post-allogeneic hematopoietic stem cell transplantation (allo-HSCT), driven by donor T cells’ dysregulated inflammation against host tissues. This limits survival and underscores the need for therapies that curb GVHD while preserving graft-versus-tumor (GVT) effects. Innate-like T cell subsets, including MAIT, NKT, and Vγ2 γδ T cells correlate with milder GVHD. These share the BTB-ZF transcription factor PLZF (Zbtb16), a master regulator of innate-like programming. Building on our finding that ectopic PLZF imparts innate-like traits to conventional αβ T cells, we tested if PLZF-overexpressing donor T cells suppress GVHD in vivo. In a B6→BALB/c acute GVHD model, lethally irradiated BALB/c recipients received bone marrow plus purified CD4+/CD8+ T cells from C57BL/6 donors, transduced with retroviral PLZF or empty vector (EV) control (n = 15/group). Mice were monitored daily for survival, clinical scores, and weight loss. In mouse models of acute GVHD (B6→BALB/c), adoptive transfer of retrovirally transduced, PLZF-overexpressing conventional T cells markedly delayed disease onset and enhanced survival relative to empty vector-transduced controls. Mechanistically, PLZF-overexpressing conventional T cell promoted expansion of regulatory T cell (Treg) populations, thereby driving a phenotypic shift toward innate-like suppression of alloimmunity. These results affirm PLZF overexpression as a viable, programmable approach for GVHD prophylaxis, poised for clinical advancement. Through innate-like T cell reprogramming, this strategy holds promise for revolutionizing allo-HSCT by decoupling immune tolerance from antitumor immunity. Current investigations are evaluating PLZF-overexpressing conventional T cell preservation of graft versus tumor (GVT) activity against leukemia and extending these findings to humanized models. NJ PHORCE Transplantation Immunology (TRAN)