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Because of the low mutational burden and consequently, fewer potential neoantigens, children with acute myeloid leukemia (AML) are thought to have a T cell-depleted or ‘cold’ tumor microenvironment and may have a low likelihood of response to T cell-directed immunotherapies. Understanding the composition, phenotype, and spatial organization of T cells and other microenvironmental populations in the pediatric AML bone marrow (BM) is essential for informing future immunotherapeutic trials about targetable immune-evasion mechanisms specific to pediatric AML. Here, we conducted a multidimensional analysis of the tumor immune microenvironment in pediatric AML and non-leukemic controls. We demonstrated that nearly one-third of pediatric AML cases has an immune-infiltrated BM, which is characterized by a decreased ratio of M2- to M1-like macrophages. Furthermore, we detected the presence of large T cell networks, both with and without colocalizing B cells, in the BM and dissected the cellular composition of T- and B cell-rich aggregates using spatial transcriptomics. These analyses revealed that these aggregates are hotspots of CD8+T cells, memory B cells, plasma cells and/or plasmablasts, and M1-like macrophages. Collectively, our study provides a multidimensional characterization of the BM immune microenvironment in pediatric AML and indicates starting points for further investigations into immunomodulatory mechanisms in this devastating disease.

Clonal evolution of leukemia is driven by different selection pressures operating on a heterogeneous population of cells. These pressures may include therapy-induced and immune-mediated effects which eradicate the majority of cells, but which simultaneously provide a selective advantage to a minor population of cells that is genetically or transcriptionally distinct and which grow out towards relapse.

Background and SignificancePediatric AML is a heterogeneous disease with current rates for event-free survival (EFS) of 50-60% and for overall survival (OS) of 70-80%, for newly diagnosed patients. In patients with refractory and relapsed disease, and in subsets as defined by AML biology and treatment response, prognosis is dismal. To further improve EFS, the NOPHO-DB-SHIP consortium has initiated trial CHIP-AML22. Building on the successes achieved by the recent trial from this consortium (NOPHO-DBH AML-2012, preliminary data as per June 2023, n=878: 5-years pEFS 63%, 5-years pOS 78%), CHIP-AML22 will incorporate innovative elements, mainly the FLT3-inhibitor quizartinib (Vanflyta®) that was recently approved by the FDA and PMDA in combination with chemotherapy for the treatment of newly diagnosed adult AML patients with FLT3-ITD mutations, and gemtuzumab ozogamicin (GO, Mylotarg ®) that improved outcome in adult and pediatric AML when added to chemotherapy. CHIP-AML22 will maintain the approach of treatment-response driven risk-adapted treatment, intensified induction treatment for patients with ≥5% AML cells in the bone marrow (BM) after course 1, and consolidation with allogeneic stem cell transplantation (allo-SCT) for high-risk patients after the first consolidation course HAM.

Pediatric acute myeloid leukemia (AML) is a cancer with a particularly low mutational burden in comparison to other pediatric and adult cancers and therefore, thought to be a poor candidate for T cell-engaging immunotherapies (Gröbner et al., 2018; Pfister et al., 2022). However, little is known about the composition and function of T cells in the bone marrow (BM) of pediatric AML patients. Insight into the frequency and function of BM T cells in children with AML is relevant for naturally occurring AML immune defenses, as well as for T cell-engaging immunotherapies (Koedijk et al., 2021). Here, we performed a multidimensional characterization of the tumor immune microenvironment in children with newly diagnosed AML.