AML halts neutrophil maturation Free

In this issue of Blood, Goel et al¹ address the impact of acute myeloid leukemia (AML) on neutrophils that results in maturation blockade and redirection toward an immunosuppressive state. Importantly, they identified that CD14 is expressed in neutrophils after the development of AML.

Although most studies on neutrophils in AML focus on the peripheral blood, Goel et al specifically evaluate neutrophils within the bone marrow (BM) microenvironment. By transplanting Mes1-HoxA9 AML cells into nonconditioned mice, they were able to monitor neutrophil reduction during AML progression using a specific lineage reporter system. Neutropenia has been well documented in patients with AML, which contributes to an increased risk of infection.^2,3 In mouse BM, neutrophils are classified into 3 subsets based on their maturation stage, distinguished by Ly6G and CD101 expression.⁴ The most immature neutrophils are Ly6G^lowCD101^–, immature neutrophils are Ly6G^highCD101^–, and mature neutrophils express both Ly6G and CD101 (Ly6G^highCD101⁺). Although all the 3 subsets are still present in the BM of mice in this AML model, mature neutrophils are significantly reduced, whereas immature subsets are increased (see figure). Similarly, Goel et al observed an increased proportion of immature neutrophils in patient BM samples. Moreover, the AML microenvironment appears to alter the transcriptomic profile of immature neutrophils by down-modulating genes associated with adaptive immune responses.

Through transcriptional and protein analyses, Goel et al identify a neutrophil subset in AML mice which expresses CD14 in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) and NF-κB activation. Although previous studies have revealed that GM-CSF and lipopolysaccharides (LPSs) can induce CD14 expression in peripheral blood neutrophils,⁵ Goel et al provide novel insights into the emergence of CD14⁺ neutrophils in BM AML microenvironment. The CD14⁺ immature neutrophils also circulate in the periphery, suggesting that CD14 could serve as a biomarker in patients. However, how CD14 relates to patient clinical characteristics and overall survival need to be further investigated.

The discovery of CD14 expression in AML BM neutrophils raises questions about the functional relevance of CD14 in neutrophil activity. Neutrophils play a key role in antimicrobial defense via phagocytosis and can also modulate T-cell responses.⁶ In solid tumors, neutrophils have been reported to suppress T cells.⁷ Similarly, Goel et al report that AML BM neutrophils have impaired capacity to support T-cell proliferation and demonstrate reduced phagocytosis activity in vitro. However, CD14⁺ neutrophils did not exhibit stronger immunosuppressive effects compared with their CD14^– counterpart, leaving open questions regarding the specific impact of CD14 upregulation on neutrophil function. On LPS stimulation, CD14⁺ neutrophils are capable of secreting tumor necrosis factor alpha.⁸ Whether CD14⁺ neutrophils in AML exhibit enhanced proinflammatory responses remains to be determined.

Interestingly, in AML, each neutrophil subset regardless of maturation stage contains a CD14⁺ fraction. Longitudinal monitoring of these CD14⁺ neutrophils would be necessary to determine the timing of CD14 expression across different maturation stages. Given the accumulation of immature neutrophils, one could speculate that CD14 expression may confer a proliferative or survival advantage to these cells. Releasing the maturation block could restore the population of functional mature neutrophils and potentially decrease the risk of infection. Therefore, targeting neutrophil dysfunction may be a promising approach to both prevent infections and enhance the cytotoxic response against AML.

Although Goel et al identified immunosuppressive neutrophils in AML, as demonstrated by impaired T-cell proliferation, the role of CD14⁺ neutrophils in modulating T-cell cytotoxicity toward AML cells will require further exploration. Understanding the immunomodulatory function of CD14⁺ neutrophils in AML requires not only transcriptional and phenotypic profiling but also spatial and temporal context within the BM. High-resolution BM imaging would offer a powerful tool to visualize the dynamic interactions between CD14⁺ neutrophils and other immune and stromal components of the microenvironment.⁹ Such insights are critical to fully decipher the mechanisms by which CD14⁺ neutrophils contribute to immune suppression or support within the AML niche.

Innate immune cells hold significant potential for improving immunotherapy outcome. However, compared with other innate immune populations, our understanding on neutrophils in the AML microenvironment remains limited.¹⁰ The findings from Goel et al expand our knowledge by revealing that neutrophil maturation is blocked in the AML BM and that CD14⁺ neutrophils emerge under these conditions. These findings support the need for further investigation into the characteristics of CD14⁺ vs CD14^– neutrophils in AML to identify mechanisms involved in maturation blockade and immunosuppressive transformation.

Conflict-of-interest disclosure: The authors declare no competing financial interests.