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. 2024 Oct;38(10):2270-2275.
doi: 10.1038/s41375-024-02387-4. Epub 2024 Aug 22.

Evolution of T-cell fitness through AML progression: enhanced bispecific T-cell engager-mediated function of bone marrow T cells at remission compared to initial diagnosis and relapse

Maryam Kazerani  1   2 , Anetta Marcinek  1   2 , Nora Philipp  1   2 , Bettina Brauchle  1   2 , Jonathan Jonas Taylor  1   2 , Helena Domínguez Moreno  3 , Andrea Terrasi  3 , Benjamin Tast  1   2 , Lisa Rohrbacher  1   2 , Yingshuai Wang  1   2 , Maximilian Warm  2 , Alica-Joana Emhardt  2 , Giulia Magno  2 , Karsten Spiekermann  2   4   5 , Tobias Herold  2 , Tobias Straub  6 , Sebastian Theurich  1   2 , Gunnar Schotta  3 , Roman Kischel  7   8 , Veit L Bücklein  1   2 , Marion Subklewe  9   10   11
Affiliations

Evolution of T-cell fitness through AML progression: enhanced bispecific T-cell engager-mediated function of bone marrow T cells at remission compared to initial diagnosis and relapse

Maryam Kazerani et al. Leukemia. 2024 Oct.
No abstract available

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Conflict of interest statement

MS has received industry research support from Amgen, BMS/Celgene, Gilead/Kite, Miltenyi Biotec, Molecular Partners, Morphosys, Novartis, Roche, Seattle Genetics, and Takeda, and has served as a consultant/scientific advisory board member at Autolus, AvenCell, CanCell Therapeutics, CDR-Life, Genmab US, Ichnos Sciences, Incyte Biosciences, Interius BioTherapeutics, Janssen, Millennium Pharmaceuticals, Miltenyi Biomedicine, Molecular Partners, Nektar Therapeutics, Novartis, Pfizer, Ridgeline Discovery, Sanofi, Scare, and Takeda. She serves on the speakers’ bureau at Amgen, AstraZeneca, BMS/Celgene, Gilead/Kite, GSK, Janssen, Novartis, Octapharma, Pfizer, Roche, Springer Healthcare, and Takeda. Educational grants were received to develop the app “MyTcell” from BMS, Gilead, Janssen, Novartis, Roche, and Takeda. VLB has received research funding from BMS, Gilead/Kite, Miltenyi Biotec, Novartis, and Roche, and has served as a consultant/advisor to Amgen, Gilead, Novartis, Pfizer, and Priothera. He serves on the speakers’ bureau at Novartis and Pfizer. RK is employed at Amgen Research Munich, Germany. ST has served as a consultant/advisor to Amgen, BMS, GSK, Janssen, Pfizer, Sanofi, and Takeda. TH has received industry research support from Roche and served as a scientific advisory board member to Servier. MK, AM (now employed by MLL Munich Leukemia Laboratory), NP, BB (now employed by Adivo), JJT (now employed by AstraZeneca), HDM (now employed by MundiCare), AT, BT, LR, YW, MW, A-JE, GM, KS, TS, and GS declare no relevant conflicts of interest. Correspondence: Marion Subklewe, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany; e-mail: marion.subklewe@med.uni-muenchen.de.

Figures

Fig. 1
Fig. 1. Bone marrow T cells at the time of ID and RL display a phenotypic and transcriptional profile of dysfunction.
A Proportions of naive (TNaive, CD45RA+CCR7+), central memory (TCM, CD45RA−CCR7+), effector memory (TEM, CD45RA−CCR7−), and terminal effector (TEMRA, CD45RA+CCR7−) T cells within the CD4+, and CD8+ compartments. B Frequency of BM CD4+ (top row) and CD8+ (bottom row) T cells positive for inhibitory receptors at ID (n = 19), RL (n = 14), CR (n = 7), and in HDs (n = 10). C Volcano plot of DEGs at ID (n = 7) vs. HDs (n = 2). Significantly upregulated (red) and downregulated (blue) genes at ID are highlighted (log2FC > 1 or < −1; P < 0.05). Selected genes are labeled. D Volcano plot of DEGs at RL (n = 7) vs. HDs (n = 2). E GSEA for gene sets associated with immune function using published gene sets derived from MSigDB or custom gene sets. GSEA statistics are provided in Supplementary Table 3. F Heatmap demonstrating selected DEGs at RL compared to ID. G GSEA in RL vs. ID T cells for gene sets associated with T-cell populations and immune function from MSigDB and published data sets (details on the gene sets are provided in the Supplementary Methods). GSEA statistics are included in Supplementary Table 6. H GSEA in RL vs. ID T cells for TFs related to TPEX and TEX. I Heatmap showing the expression of top hits, from the analysis in panel H, in ID and RL patients. J TF motifs enriched in RL-specific ATAC peaks. Significant motifs are labeled and highlighted in red. K ATAC-seq tracks of selected genes significantly upregulated in RL vs. ID T cells. BM bone marrow, CR complete remission, DEG differentially expressed gene, GSEA gene set enrichment analysis, HD healthy donor, ID initial diagnosis, RL relapse, TF transcription factor. All plots represent the mean ± SEM. One-way ANOVA was used to calculate P values.
Fig. 2
Fig. 2. ID T cells display lower BiTE-mediated cytotoxicity compared to RL, but both have impaired metabolic fitness after continuous stimulation.
A AMG 330-mediated cytotoxicity of T cells sampled at ID (n = 8), RL (n = 7), and CR (n = 6) on day 5 against OCI-AML3 cells relative to cBiTE (concentration AMG 330 or cBiTE = 5 ng/ml, E:T = 1:3). B T-cell proliferation on day 5 calculated as fold change relative to the number of T cells on day 0. C Percentage of T cells producing GZMB measured by flow cytometry after intracellular staining on day 5. D AMG 330-mediated cytotoxicity of T cells sampled at ID (n = 10) and RL (n = 7) against autologous primary AML blasts in ex vivo cytotoxicity assays (concentration AMG 330 or cBiTE = 5 ng/ml) on day 6. E T-cell proliferation on day 6 calculated as fold change relative to the number of T cells on day 0. F Percentage of CD4+ and CD8+ T cells from patients at ID (n = 6), RL (n = 6), and CR (n = 4) co-expressing PD-1, Tim-3, and LAG-3 on day 14 of continuous stimulation. G AMG 562-mediated cytotoxicity of isolated T cells against OCI-Ly1 cells after 14 days of continuous stimulation (concentration AMG 562 or cBiTE = 5 ng/ml, E:T = 1:5, 3 days). H Levels of secreted TNF, IFN-γ, and GZMB measured by CBA in the supernatants of cytotoxicity assays on day 3. I Kinetic plot and corresponding bar graphs of normalized OCR acquired during mitochondrial stress testing of T cells from patients at ID (n = 4), RL (n = 5), and CR (n = 4) after 14 days of continuous stimulation with AMG 562. J Kinetic plot and corresponding bar graphs of normalized ECAR obtained during glycolysis stress testing of T cells from patients at ID (n = 4), RL (n = 5), and CR (n = 4) after 14 days of continuous stimulation with AMG 562. CR complete remission; ID initial diagnosis, RL relapse. Bar plots represent the mean ± SEM. One-way ANOVA (A–C and F–J) and Mann–Whitney tests (D, E) were used to calculate P values.
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