Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease

Abstract

Trained immunity (TI) is a pro-inflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and characterized by immunometabolic and epigenetic changes enhancing cytokine production. Maladaptive activation of TI (i.e., in the absence of infection) might result in detrimental inflammation and disease development; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. Here, we reveal oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, ECD, characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production). Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mTOR signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyper-inflammatory responses. In ECD patients, effective therapeutic strategies contrast this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (i.e., glycolysis) effectively dampens cytokine production by myeloid cells. This study reveals the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms, and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.

Impact of BRAFV600E mutation on aggressiveness and outcomes in adult clonal histiocytosis

“…In LCH, BRAF V600E mutation in bone marrow progenitors gives rise to mutated clones infiltrating myeloid dendritic cells, which infiltrate virtually all tissues (16). The same mechanism is proposed in ECD with a predominant involvement of CD14+ monocytes (17) rather than dendritic cells and also an abnormal activation of "trained immunity" mediated by BRAF (18). The understanding of the brain involvement mechanism has yet to be elucidated.…”

“…Disease activity was assessed using 18 fluorodeoxyglucose positron tomography (according to Positron Emission Tomography Response Criteria In Solid Tumors (PERCIST) criteria). Complete metabolic response was defined by the normalization of all lesions to at or below the standardized uptake value (SUV) of the liver background.…”

Pancreatic involvement in Erdheim-Chester disease: a case report and review of the literature

“…Recently, two recent publications have explained the cause of the hyperinflammatory state in ECD and other histiocytic diseases. Molteni, R. and his colleagues found that BRAF V600E in macrophages induce hallmark immunometabolic features of trained immunity, causing activation of the AKT/mTOR signaling axis, increased glycolysis, epigenetic changes on promoters of genes encoding cytokines, and enhanced cytokine production leading to hyper-inflammatory responses [ 14 ]. Biavasco, R. and his colleagues discovered that the activation of BRAF V600E impairs HSPC function, features myeloid restricted hematopoiesis, and leads to a widespread inflammatory condition [ 15 ].…”

3D tumor explant as a novel platform to investigate therapeutic pathways and predictive biomarkers in cancer patients

“…In addition, simulated microgravity influenced metabolic pathways, such as lipid metabolism and the Krebs cycle in human breast cancer cells, osteoblasts, oligodendrocytes and gastric cancer cells (51)(52)(53)(54). Of note, metabolomic analysis of supernatants of Erdheim-Chester disease (ECD) biopsies cultured for 4 days in RCCS Bioreactor revealed that the immunometabolic changes of trained immunity occurring in ECD lesions in vivo, such as increased glycolysis and accumulation of fumarate and malate, can be dampened by MAPK pathway inhibition (55). A recent study in gastric cancer showed that PDE culture in RCCS bioreactor recapitulates the action of chemotherapy in patients by affecting cell survival and by weakening the action of drug resistanceassociated genes (56).…”