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Oncogene-induced TIM-3 ligand expression dictates susceptibility to anti-TIM-3 therapy in mice.


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 TIM-3 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.

SUBMITTER: Talvard-Balland N 

PROVIDER: S-EPMC11324309 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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Oncogene-induced TIM-3 ligand expression dictates susceptibility to anti-TIM-3 therapy in mice.

Talvard-Balland Nana N   Braun Lukas M LM   Dixon Karen O KO   Zwick Melissa M   Engel Helena H   Hartmann Alina A   Duquesne Sandra S   Penter Livius L   Andrieux Geoffroy G   Rindlisbacher Lukas L   Acerbis Andrea A   Ehmann Jule J   Köllerer Christoph C   Ansuinelli Michela M   Rettig Andres A   Moschallski Kevin K   Apostolova Petya P   Brummer Tilman T   Illert Anna L AL   Schramm Markus A MA   Cheng Yurong Y   Köttgen Anna A   Duyster Justus J   Menssen Hans D HD   Ritz Jerome J   Blazar Bruce R BR   Boerries Melanie M   Schmitt-Gräff Annette A   Sariipek Nurefsan N   Van Galen Peter P   Buescher Joerg M JM   Cabezas-Wallscheid Nina N   Pahl Heike L HL   Pearce Erika L EL   Soiffer Robert J RJ   Wu Catherine J CJ   Vago Luca L   Becher Burkhard B   Köhler Natalie N   Wertheimer Tobias T   Kuchroo Vijay K VK   Zeiser Robert R  

The Journal of clinical investigation 20240625 16


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 TIM-3 ligand exp  ...[more]

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