Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment

Abstract

Background Knowledge of immune cell phenotypes, function, and developmental trajectory in acute myeloid leukemia (AML) microenvironment is essential for understanding mechanisms of evading immune surveillance and immunotherapy response of targeting special microenvironment components. Methods Using a single-cell RNA sequencing (scRNA-seq) dataset, we analyzed the immune cell phenotypes, function, and developmental trajectory of bone marrow (BM) samples from 16 AML patients and 4 healthy donors, but not AML blasts. Results We observed a significant difference between normal and AML BM immune cells. Here, we defined the diversity of dendritic cells (DC) and macrophages in different AML patients. We also identified several unique immune cell types including T helper cell 17 (TH17)-like intermediate population, cytotoxic CD4+ T subset, T cell: erythrocyte complexes, activated regulatory T cells (Treg), and CD8+ memory-like subset. Emerging AML cells remodels the BM immune microenvironment powerfully, leads to immunosuppression by accumulating exhausted/dysfunctional immune effectors, expending immune-activated types, and promoting the formation of suppressive subsets. Conclusion Our results provide a comprehensive AML BM immune cell census, which can help to select pinpoint targeted drug and predict efficacy of immunotherapy.

Macrophages in Acute Myeloid Leukaemia: Significant Players in Therapy Resistance and Patient Outcomes

“…This is in line with Yang et al (2017) ’s results, showing decreased probability of survival in AML patients with high CD163 transcript levels (as well as CD206, CD163 also used to define M2-like Mφs), as compared to patients with lower CD163 levels. Further confirming the association of CD163 with poor clinical outcomes, Guo et al (2021) described the association of a distinct monocyte/macrophage cluster by single-cell RNAseq, highly expressing CD163, with reduced probability of survival in AML patients ( Guo et al, 2021 ). Interestingly, Xu et al (2019) also showed that the frequency of M1-like Mφs, in cohort 3 (GSE6891, this study included 461 blood and bone marrow samples from AML patients, under the age of 60, with gene expression analysed via an Affymetrix GeneChip TM Human Genome U133 Plus 2.0 Array), arose as the sole and significant prognosticator for prolonged survival in AML patients.…”

“…Therefore, the authors could not completely rule out the possible contribution of CD206 + DCs in their study. Complementing this work, is the study by Guo et al (2021) , describing the enrichment of two potentially immunosuppressive DC populations in AML BM, compared to a healthy BM. These were shown to be CD206 + DCs, associated with recruitment of regulatory T-cell populations, and T-cell suppressive CX3CR1 + DCs.…”

“…Despite the observation from another study demonstrating that CD163 + and CD206 + macrophage populations were found to be infrequently enriched in AML BM samples, analysis at the single cell level will aid in identifying rare cell types that, when found alone or in association with other immune cell types, may exacerbate disease pathogenesis and therefore negatively impact patient prognosis ( Guo et al, 2021 ). Consequently, further studies are required to fully ascertain the contribution of both bona fide non-malignant, as well as malignant/AML M2 and M1-like monocytes/Mφs in AML pathogenesis, and to determine if the M1/M2 ratio has potential as a prognosticator for outcome and treatment response in AML.…”

Catch me if you can: how AML and its niche escape immunotherapy

“…Tumor escape strategies in AML involve direct adaptation of the AML cells to hide from immune recognition and tumor-cell-mediated modifications of the immune cell compartment that include effector T cells, natural killer cells (NKs), and dendritic cells (DCs). With the advent of spatially-resolved immunohistochemistry, high-throughput single-cell transcriptomic, proteomic, and mass cytometry technologies it is possible to better decipher the AML immunologic microenvironment and to envision more tailored immunotherapeutic strategies for the future of AML treatment [1][2][3][4][5].…”

“…Representative mechanisms by which AML-reprogrammed niche cells can promote immune evasion. Mesenchymal stromal cells (MSCs) can regulate the immune response in the leukemic BM microenvironment by secreting a plethora of inhibitory factors, as soluble molecules or as a component of exosomes(1). These factors can inhibit cell proliferation, cytolysis, and production of anti-leukemia cytokines by effector lymphocytes.…”