Session: 618. Acute Lymphoblastic Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Translational Research, genomics, Diseases, immune mechanism, immunology, Lymphoid Malignancies, Biological Processes, pathogenesis
To delineate the tumor microenvironment (TME) features of ORM1 high B-ALL through digital cytometry, we constructed a novel bone marrow signature matrix that recapitulates the native BM cellular landscape, including hematopoietic progenitors and mesenchymal stem cells, and performed de novo transcriptional subtype discovery agnostic to clinical outcomes using the Ecotyper platform on a cohort of 577 B-ALL microarray transcriptomes from the MILE study (GSE13159). Discovery analysis identified 51 transcriptionally defined TME cell states across 17 cell types. ORM1 overexpression significantly correlated with transcriptionally-distinct neutrophil, promyelocyte, monocyte, and macrophage subsets enriched for immunosuppressive gene expression programs as well as CD8+ and γδ T-cell subsets with hallmark transcriptional features of effector dysfunction and exhaustion. To validate the imputed cell states at single-cell resolution and define their immunophenotypic features, we drew upon several B-ALL CITE-seq datasets. Recovery and assignment of discovery cohort transcriptional states to single-cell transcriptomes in KMT2A-r and Ph+ cases confirmed enrichment for multiple myeloid-derived suppressor cell (MDSC) and dysfunctional T-cell transcriptional subsets. MDSCs were predominantly monocytic but also included neutrophilic promyelocytes with surface expression of CD123 and CD155/PVR, which interacts with TIGIT to suppress immune cell activation. Indeed, enrichment for CD8+ cytotoxic lymphocytes with surface expression of PD-1 and TIGIT was also present. Neutrophilic MDSCs were present at diagnosis, in pre-relapse remission samples and at the time of relapse, suggesting that their persistence following frontline therapy may facilitate the immune evasion and expansion of treatment-resistance leukemic clones that drive eventual relapse.
Taken together, high ORM1 expression marks a subset of high-risk B-ALL characterized by enrichment for transcriptionally-distinct immunosuppressive TME cell states which may be targetable with emerging therapeutic strategies aimed at restoring host anti-tumor immunity.
Disclosures: No relevant conflicts of interest to declare.
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