Abstract A046: Dendritic cell dysfunction predicts adverse prognosis in high-risk acute lymphoblastic leukemia

Abstract Dendritic cells (DCs) are a rare but critical component of anticancer defense. Perturbations in DCs in B/T-cell acute lymphoblastic leukemia (ALL), their cause(s) and consequence(s) on antileukemia immunity and patient outcome have not been thoroughly explored. Using high-dimensional flow cytometry and single-cell RNA sequencing (scRNA-seq), we profiled peripheral blood (PBMC) and bone marrow (BMMC) samples from 33 high-risk ALL patients and 35 tissue-matched healthy donors. We found significant defects in DC homeostasis that can predict clinical outcome at leukemia presentation. We found maturation of DC1-6 subsets to be disrupted in both children and adults with ALL. Within these subsets, conventional DC (cDC) subsets 1-3 showed greatest disruption with aberrant expression of subtype-specific markers. Computational lineage tracing using CellRANK identified ‘DC precursor-like’ cells within the peripheral DC4 fraction of healthy donors, which were aberrantly expanded in patients with ALL. DCs in ALL deviated from canonical maturation trajectories and had reduced expression of key transcription factors (IRF8 and IRF4), and cytokines receptors (e.g., CD116) required for their homeostatic development. Thus, the specialization of DCs into distinct functional lineages is impaired in ALL. Consistent with their perturbed functional specialization, antigen-primed ALL cDCs failed to induce T-cell proliferation when co-cultured with healthy donor pan-T cells, unlike healthy donor-derived DCs. Because elevated expressions of HLA-DR and CD11c on cDCs mark their mature stage with T-cell priming potential, we asked whether these markers are perturbed during primary human and murine leukemogenesis. In samples from patients and two preclinical ALL mouse models, CD11cHighHLA-DRHigh mature DCs were reduced at the expense of CD11cLowHLA-DRLow/- DCs. Interestingly, overexpression of MYC oncogene in ALL cells reduces the frequencies of CD11cHighHLA-DRHigh mature DCs and impairs their ability to induce T cell proliferation. Finally, we examined the prognostic significance of the defects in DCs in patients with ALL. In the ALL-patient cohort in which we identified defects in DCs, reduced frequencies of CD11cHighHLA-DRHigh DCs was associated with reduced overall survival (P<0.05). In an independent cohort of patients from the Children’s Oncology Group (COG) P9906 trial, children with increased frequencies of cells with a ‘dysfunctional DC’ transcriptome had inferior outcomes compared to their counterparts with ‘functional DC’ transcriptome (P<0.05). In conclusion, defective DC maturation impairs T-cell proliferation and subsequent surveillance and serves as an important predictor of poor patient outcome. Citation Format: Anil Kumar, Kory Hamane, Caroline Duault, Joao Rodrigues. Lima-Junior, Da Hae Jung, Hanjun Qin, Sheyla Salcido, Min Huang, Xinying Guo, Adeleh Taghi. Khani, Ashly Sanchez. Ortiz, Lucy Ghoda, Guido Marcucci, Norman J. Lacayo, Kathleen M. Sakamoto, Christian Hurtz, Martin Carroll, Sarah K. Tasian, Huimin Geng, Lingyun Ji, Saro Armenian, Shai Izraeli, Xiwei Wu, Holden T. Maecker, Srividya Swaminathan. Dendritic cell dysfunction predicts adverse prognosis in high-risk acute lymphoblastic leukemia [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A046.