Oncogene-induced TIM-3 ligand expression dictates susceptibility to anti–TIM-3 therapy in mice
Year: 2024
Type: article
Abstract: Leukemia relapse is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). We tested the potential of targeting T cell (Tc) immunoglobulin and mucin-containing molecule 3 (TIM-3) for improving graft-versus-leukemia (GVL) effects. We observed differential expression of TIM-3 ligands when hematopoietic stem cells overexpressed certain oncogenic-driver mutations. Anti–TIM-3 Ab treatment improved survival of mice bearing leukemia with oncogene-induced TIM3 ligand expression. Conversely, leukemia cells with low ligand expression were anti–TIM-3 treatment resistant. In vitro, TIM-3 blockade or genetic deletion in CD8+ Tc enhanced Tc activation, proliferation, and IFN-γ production while enhancing GVL effects, preventing Tc exhaustion, and improving Tc cytotoxicity and glycolysis in vivo. Conversely, TIM-3 deletion in myeloid cells did not affect allogeneic Tc proliferation and activation in vitro, suggesting that anti–TIM-3 treatment–mediated GVL effects are Tc induced. In contrast to anti–programmed cell death protein 1 (anti–PD-1) and anti–cytotoxic T lymphocyte–associated protein 4 (anti–CTLA-4) treatment, anti–TIM-3-treatment did not enhance acute graft-versus-host disease (aGVHD). TIM-3 and its ligands were frequently expressed in acute myeloid leukemia (AML) cells of patients with post–allo-HCT relapse. We decipher the connections between oncogenic mutations found in AML and TIM-3 ligand expression and identify anti–TIM-3 treatment as a strategy for enhancing GVL effects via metabolic and transcriptional Tc reprogramming without exacerbation of aGVHD. Our findings support clinical testing of anti–TIM-3 Ab in patients with AML relapse after allo-HCT.
Authors: Talvard-Balland, Nana, Braun, Lukas M., Dixon, Karen O., Zwick, Melissa, Engel, Helena, Hartmann, Alina, Duquesne, Sandra, Penter, Livius, Andrieux, Geoffroy, Rindlisbacher, Lukas, Acerbis, Andrea, Ehmann, Jule, Köllerer, Christoph, Ansuinelli, Michela, Rettig, Andres, Moschallski, Kevin, Apostolova, Petya, Brummer, Tilman, Illert, Anna L., Schramm, Markus A., Cabezas Wallscheid, Nina, et al.
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W6891317344
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