Inflammatory response mediates cross-talk with immune function and reveals clinical features in acute myeloid leukemia

Abstract

Accumulated genetic mutations are an important cause for the development of acute myeloid leukemia (AML), but abnormal changes in the inflammatory microenvironment also have regulatory effects on AML. Exploring the relationship between inflammatory response and pathological features of AML has implications for clinical diagnosis, treatment and prognosis evaluation. We analyzed the expression variation landscape of inflammatory response-related genes (IRRGs) and calculated an inflammatory response score for each sample using the Gene set variation analysis (GSVA) algorithm. The differences in clinical- and immune-related characteristics between high- and low-inflammatory response groups were further analyzed. We found that most IRRGs were highly expressed in AML samples, and patients with high inflammatory response had poor prognosis and were accompanied with highly activated chemokine-, cytokine- and adhesion molecule-related signaling pathways, higher infiltration ratios of monocytes, neutrophils and M2 macrophages, high activity of type I/II interferon (IFN) response, and higher expression of immune checkpoints. We also used the Genomics of Drug Sensitivity in Cancer (GDSC) database to predict the sensitivity of AML samples with different inflammatory responses to common drugs, and found that AML samples with low inflammatory response were more sensitive to cytarabine, doxorubicin, and midostaurin. Finally, we constructed a prognostic risk-score model to predict the overall survival (OS) of AML patients. Patients with higher risk score had significantly shorter OS, which was confirmed in two validation cohorts. The analysis of inflammatory response patterns can help us better understand the differences in tumor microenvironment of AML patients, and guide clinical medication and prognosis prediction.

T cell-mediated tumor killing sensitivity gene signature-based prognostic score for acute myeloid leukemia

“…T cell exhaustion and concurrent PD-1 resistance is a characteristic of severe AML [ 67 , 68 ]. An AML tumor immune landscape marked by high M2 macrophage and monocyte infiltration corresponds to high inflammatory response and predicts poor survival [ 69 ], in alignment with our results.…”

Effects of Combinatory In Vitro Treatment with Immune Checkpoint Inhibitors and Cytarabine on the Anti-Cancer Immune Microenvironment in De Novo AML Patients

“…Immunosuppressive cytokines, such as IL-10 or TGF-beta, have been to date predominantly considered as unfavourable elements in leukaemia in the presence of their excess. In contrast, pro-inflammatory IL-1beta and IL-6 were expected to demonstrate active anti-tumour activity [42,43]. We were not able to separate the blast-and lymphocyterelated production of the mentioned cytokines; thus, we reported that IL-6 could originate from both populations [44].…”

Studying Signaling Pathway Activation in TRAIL-Resistant Macrophage-Like Acute Myeloid Leukemia Cells

“…The data on the activation of inflammatory processes in the bone marrow microenvironment in AML [ 5 , 6 , 60 ] and the role of cytokine IL1ß in the progression of myeloid leukemia have been reported [ 51 , 61 , 62 ]. In addition, macrophage differentiation is accompanied by increased expression of the cIAP2 protein [ 63 ].…”

“…It is well known that in acute myeloid leukemia, the bone marrow acquires the characteristics of damaged tissue, with signs of chronic inflammation [ 3 , 4 ]. The inflammatory process in the bone marrow contributes to the avoidance of tumor cell death induced by both antitumor drugs and components of antitumor immunity; therefore, it is a marker of an unfavorable prognosis in the course of the disease [ 5 , 6 , 7 ]. It is also known that under inflammatory conditions, activation of proinflammatory intracellular signaling pathways can lead to myeloid differentiation of healthy hematopoietic progenitor cells [ 8 , 9 , 10 ].…”