A Metabolic Reprogramming Amino Acid Polymer as an Immunosurveillance Activator and Leukemia Targeting Drug Carrier for T‐Cell Acute Lymphoblastic Leukemia

• Published in: Advanced science 2022-03, Vol.9 (9), p.e2104134-n/a
• Main Authors: Li, Changzheng, You, Xinru, Xu, Xi, Wu, Binghuo, Liu, Yuye, Tong, Tong, Chen, Jie, Li, Yishan, Dai, Chunlei, Ye, Zhitao, Tian, Xiaobin, Wei, Yan, Hao, Zechen, Jiang, Linjia, Wu, Jun, Zhao, Meng
• Format: Article
• Language: English
• Subjects: amino acid metabolism; Amino Acids; Animals; Bone marrow; Cancer therapies; Cardiotoxicity; Chemotherapy; Chromatography; Drug Carriers; Hematology; immunosurveillance; Leukemia; Metabolic Reprogramming Immunosurveillance Activation Nanomedicine (MRIAN); Metabolism; Metabolites; Mice; Monitoring, Immunologic; myeloid‐derived suppressor cells (MDSCs); NMR; Nuclear magnetic resonance; Particle size; Pharmacokinetics; Polymers; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; T-Lymphocytes; T‐cell acute lymphoblastic leukemia (T‐ALL); Variance analysis
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202104134

Compromised immunosurveillance leads to chemotherapy resistance and disease relapse of hematological malignancies. Amino acid metabolism regulates immune responses and cancer; however, a druggable amino acid metabolite to enhance antitumor immunosurveillance and improve leukemia targeting‐therapy efficacy remains unexplored. Here, an L‐phenylalanine polymer, Metabolic Reprogramming Immunosurveillance Activation Nanomedicine (MRIAN), is invented to effectively target bone marrow (BM) and activate the immune surveillance in T‐cell acute lymphoblastic leukemia (T‐ALL) by inhibiting myeloid‐derived suppressor cells (MDSCs) in T‐ALL murine model. Stable‐isotope tracer and in vivo drug distribution experiments show that T‐ALL cells and MDSCs have enhanced cellular uptake of L‐phenylalanine and MRIANs than normal hematopoietic cells and progenitors. Therefore, MRIAN assembled Doxorubicin (MRIAN‐Dox) specifically targets T‐ALL cells and MDSCs but spare normal hematopoietic cells and hematopoietic stem and progenitor cells with enhanced leukemic elimination efficiency. Consequently, MRIAN‐Dox has reduced cardiotoxicity and myeloablation side effects in treating T‐ALL mice. Mechanistically, MRIAN degrades into L‐phenylalanine, which inhibits PKM2 activity and reduces ROS levels in MDSCs to disturb their immunosuppressive function and increase their differentiation toward normal myeloid cells. Overall, a novel amino acid metabolite nanomedicine is invented to treat T‐ALL through the combination of leukemic cell targeting and immunosurveillance stimulation. It is shown Metabolic Reprogramming Immunosurveillance Activation Nanomedicine (MRIAN) targets T‐cell acute lymphoblastic leukemia (T‐ALL) cells and myeloid‐derived suppressor cells (MDSCs) in the bone marrow (BM). MRIAN degrades into L‐Phe to reprogram the energy metabolism of MDSCs, which drives their differentiation toward normal myeloid cells and unarms their immunosuppressive function to reinforce immune surveillance in T‐ALL.