Exercise Delays Human Leukemia Progression and Mitigates Graft-Versus-Host Disease After Donor Lymphocyte Infusion in Xenogeneic Mice.

Donor lymphocyte infusion (DLI) is employed to enhance the graft-versus-leukemia (GvL) effect and improve remission rates following allogeneic hematopoietic cell transplantation (alloHCT). However, graft-versus-host disease (GvHD) remains a significant complication of both alloHCT and DLI. Regular exercise has been shown to reduce cancer risk, enhance treatment responses, and mitigate therapy-related toxicities. This study investigated the effects of voluntary wheel running on GvL and GvHD following DLI in a xenogeneic mouse model. Immunodeficient NSG-IL15 mice were challenged with a luciferase-expressing chronic myelogenous leukemia cell line (K562), and then they received DLI with peripheral blood mononuclear cells (PBMCs) from healthy volunteers (GvL model). Non-tumor bearing mice received DLI to model GvHD. Half of the mice in each group were then given free access to a running wheel. Tumor growth (bioluminescence), GvHD, and body weight were monitored biweekly for ~40 days. In the GvHD model, exercise extended overall survival by 60% and reduced GvHD severity. In the GvL model, exercise significantly lowered tumor burden and extended tumor-free survival in both DLI and vehicle control groups by 44.5% and 37.5%, respectively, suggesting both immune-dependent and immune-independent mechanisms. RNA sequencing of bone marrow from saline-injected mice revealed that genes associated with mitochondrial function, protein synthesis, and metabolic processes were downregulated in tumors from exercised mice. In summary, voluntary wheel running improved DLI outcomes by enhancing GvL and reducing GvHD. These benefits may be mediated, in part, through exercise-induced metabolic reprogramming of leukemia cells.