Oncogene-induced TIM-3 ligand expression dictates susceptibility to anti–TIM-3 therapy in mice
Nana Talvard-Balland, … , Vijay K. Kuchroo, Robert Zeiser
Nana Talvard-Balland, … , Vijay K. Kuchroo, Robert Zeiser
Published June 25, 2024
Citation Information: J Clin Invest. 2024;134(16):e177460. https://doi.org/10.1172/JCI177460.
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Research Article

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.

Authors

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

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Figure 6

Anti–TIM-3 treatment leads to recall immunity against AML cells without inducing aGVHD.

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Anti–TIM-3 treatment leads to recall immunity against AML cells without ...
(A) Kaplan-Meier plot showing mouse survival in the indicated groups. C57BL/6 recipient mice were injected with FLT3-ITD MLL-PTD AML cells and 5 × 106 allogeneic BM. At day 2, mice received adoptive transfer of 3 × 105 allogeneic donor Tc. Allogeneic Tc were isolated on day 15 from FLT3-ITD MLL-PTD AML–bearing mice, which received allogeneic BM/Tc and were treated with isotype (n = 14) or anti–TIM-3 (n = 14) Ab. (B–D) The scatter plots show the histopathological aGVHD severity in the indicated groups. BALB/c recipient mice were injected i.v. with 5 × 106 allogeneic BM and 4 × 105 allogeneic Tc. From day 1 to day 5, mice were treated (150 μg, i.p.) with anti–TIM-3/isotype, anti–PD-1/isotype, or anti–CTLA-4 isotype. aGVHD histological scores were determined on liver, SI, and colon at day 7 for the different groups. Data are represented as mean ± SEM from 2 independent experiments. P values were calculated using an unpaired Student’s t test.