Spatial analysis reveals distinct immune phenotypes and tertiary lymphoid structure-like aggregates in pediatric acute myeloid leukemia

Abstract

Pediatric cancers are characterized by a relatively low mutational burden and therefore, children are thought to be poor candidates for T cell-engaging immunotherapies. Here, we performed a multidimensional characterization of the tumor immune microenvironment in newly diagnosed children with acute myeloid leukemia (AML) and non-leukemic controls. We identified a subset of pediatric AML patients with remarkably high levels of T cell infiltration and a relatively low abundance of anti-inflammatory macrophages. In addition, we detected large T cell networks that colocalized with B cells in the bone marrow of immune-infiltrated samples, resembling tertiary lymphoid structures as described in solid tumors. Using spatial transcriptomics, we dissected the composition of these structures and revealed unique hotspots of anti-tumor immunity. This work raises the possibility that a subset of pediatric AML patients may benefit from T cell-engaging immunotherapies and encourages further study of these lymphoid structures in the context of immunotherapy in AML.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

NCT02152956

Funding Statement

This work has been funded in part by a KIKA (329) program grant to O.H.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study complies with all relevant ethical regulations and was approved by the Institutional Review Board of the Princess Maxima Center for Pediatric Oncology (PMCLAB2021.207 & PMCLAB2021.238) and the Scientific Committee of the Dutch Nationwide Pathology Databank (PALGA: lzv2021-82; Casparie et al., 2007). All patients treated at the Princess Maxima Center provided written consent for banking and research use of these specimens, according to the Declaration of Helsinki. Bone biopsy tissues acquired from external biobanks (n=28) were leftover material from standard care procedures and therefore, no informed consent was acquired, according to Dutch legislation and the code of conduct of the Committee on Regulation of Health Research (COREON).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

Upon publication, sequencing data can be accessed from the Gene Expression Omnibus (nCounter data: GSEXXX; GeoMx data: GSEXXX; both normalized counts) and from the European Genome-phenome Archive (EGA) database (https://ega-archive.org/studies/EGAXXX; raw nCounter and GeoMx data).

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