Artesunate Switches Monocytes to an Inflammatory Phenotype with the Ability to Kill Leukemic Cells

Abstract

Monocytes are components of the tumor microenvironment related to cancer progression and immune escape. Therapeutic strategies for reprogramming monocytes from a tumor-supporting phenotype towards a tumoricidal phenotype are of great interest. Artesunate (ART) may be an interesting option for cancer treatment; however, the role of ART in regulating the inflammatory tumor microenvironment has not yet been investigated. Our aim is to evaluate the immunomodulatory potential of ART in vitro in human primary monocytes. ART treatment induced an increase in inflammatory monocytes (CD14highCD16−) with HLA-DR high expression and MCP-1/IL-1β release. On the other hand, ART treatment reduced CD206 and CD163 expression, and abolished the monocyte population known as non-classical and intermediate. Leukemia cells in contact with monocytes programmed with ART presented enhanced in vitro apoptosis suggesting that monocytes acquired the ability to kill leukemic cells. ART induced changes in the monocyte phenotype were mediated by JAK2/STAT3 downregulation. The induction of immunosuppressive environment is an important step for cancer progression. ART showed an immunomodulatory activity, leading immune cells to an antitumor phenotype and could be a candidate for immunotherapy in cancer patients.

Targeting Inhibition of Accumulation and Function of Myeloid-Derived Suppressor Cells by Artemisinin via PI3K/AKT, mTOR, and MAPK Pathways Enhances Anti-PD-L1 Immunotherapy in Melanoma and Liver Tumors

“…Dihydroartemisinin, one of ART derivatives, strengthens γδT cell killing activities against pancreatic cancer cells through increasing intracellular perforin, granzyme B, and IFN-γ production signaling pathways [49]. In addition, artesunate, another ART derivative, enables tumor-associated monocytes to repolarize tumoricidal inflammatory monocytes against leukemic cells by inhibition of JAK2/STAT3 pathway [50]. Interestingly, the nanoparticles encapsulated chemotherapeutic drug oxaliplatin, and dihydroartemisinin significantly enhances the tumor antigen uptake and presentation of both dendritic cells and macrophages through MHC I signals in colorectal tumor-bearing mice [51].…”

The Role of Tumor-Associated Macrophages in Hematologic Malignancies

“…Artesunate (ART) induced an increase in inflammatory monocytes in vitro, while it reduced macrophage expression of CD206 and CD163. After contact with monocytes reprogrammed by ART, the in vitro apoptosis of leukemic cells was increased, due to ART changing the monocyte phenotype by JAK2/STAT3 downregulation [ 167 ].…”

Approaches of the Innate Immune System to Ameliorate Adaptive Immunotherapy for B-Cell Non-Hodgkin Lymphoma in Their Microenvironment

“…Moreover, artesunate treatment reduced CD206 and CD163 expression and abolished the non-classical monocyte population (CD14 − CD16 high ), while decreasing the intermediate subset (CD14 high CD16 + ). This phenotypic change in monocytes was attributed to reduced phosphorylation of Janus kinase 2 (JAK2) and STAT3 [ 83 ].…”