Oncogene-induced TIM-3 ligand expression dictates susceptibility to anti–TIM-3 therapy in mice
Nana Talvard-Balland, et al.
Nana Talvard-Balland, et al.
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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 8

Expression of TIM-3 and its ligands in human primary samples.

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Expression of TIM-3 and its ligands in human primary samples. (A) Overvi...
(A) Overview of UMAP embedding colored by 27 projected cell types of 574,502 scRNA-Seq profiles from van Galen et al. (50) (n = 20,362), Abbas et al. (52) (n = 127,027), Huo et al. (54) (n = 20,385), Beneyto-Calabuig et al. (51) (n = 101,767), and Penter et al. (53) (n = 304,961). Major cell types are highlighted. (B) Scaled gene expression of HAVCR2, CEACAM1, HMGB1, LGALS9, and PTDSS1 across AML BM scRNA-Seq profiles. AML BM cases include newly diagnosed and relapsed disease with or without allo-HCT. (C) Proportion of TIM-3+ cells of all NK cells across normal and AML BM data sets. (D) Heatmap generated from scRNA-Seq profiles from van Galen et al. (50) showing expression of HAVCR2, LGALS9, and HMGB1 in normal hematopoiesis and AML cell types of patients at diagnosis of AML. (E) Expression of HAVCR2, LGALS9, CEACAM1, and HMGB1 in human AML cells determined by bulk RNA-Seq. AML cells were isolated from patients with AML relapse after allo-HCT at multiple transplant centers. (F) Probability of survival stratified according to high versus low HAVCR2 gene expression in AML BM at diagnosis within the target-AML cohort (58). RNA-Seq data were derived from the GenomicDataCommons (GDC) library (https://gdc.cancer.gov/). Gene expression more than 1 SD above mean was defined as high expression.