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

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; Cheng, Yurong; Köttgen, Anna; Duyster, Justus; Menssen, Hans D; Ritz, Jerome; Blazar, Bruce R; Boerries, Melanie; Schmitt-Gräff, Annette; Sariipek, Nurefsan; Van Galen, Peter; Buescher, Joerg M; Cabezas-Wallscheid, Nina; Pahl, Heike L; Pearce, Erika L; Soiffer, Robert J; Wu, Catherine J; Vago, Luca; Becher, Burkhard; Köhler, Natalie; Wertheimer, Tobias; Kuchroo, Vijay K; Zeiser, Robert     «

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; Cheng, Yurong; Köttgen, Anna; Duyster, Justus; Menssen, Hans D; Ritz, Jerome; Blazar, Bruce R; Boerries, Melanie; Schmitt-Gräff, Annette; Sar...     »

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.      «

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...     »