Therapeutic targeting of metabolic interactions between cancer and immune cells to improve the graft-versus-leukemia effect

• Applicant: Professorin Dr. Petya Apostolova
• Subject Area: Hematology, Oncology ; Immunology
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 492259164

Acute myeloid leukemia (AML) is a malignant disease characterized by an uncontrolled proliferation of myeloblasts in the bone marrow leading to an aggressive clinical course in most patients. One potent curative treatment option for AML is allogeneic hematopoietic cell transplantation (allo-HCT), in which alloreactive T cells from a foreign donor eliminate residual leukemia cells. This process is termed graft-versus-leukemia effect (GVL). However, a significant percentage of allo-HCT recipients develop an AML relapse. AML relapse can be treated by administering donor lymphocyte infusions (DLI) in combination with cytotoxic drugs, but the success of this approach is limited. One possible mechanism that leads to immune evasion of AML cells is an altered metabolism resulting from selection pressure by the cytotoxic treatment and the donor immune system. Recognizing which metabolic pathways are employed by therapy-surviving AML cells could offer novel targets to strengthen the GVL effect.In preliminary experiments I observed that chemotherapy-resistant AML cells rewired their metabolism during recovery from cytotoxic stress. These cells accumulated several metabolites, including hexosamine biosynthesis pathway endpoint UDP-GlcNAc, which is essential for post-translational glycosylation of proteins, as well as the energy-rich metabolites creatine and phosphocreatine. Data from gene expression analysis and CRISPR-Cas9-induced deletion models suggested that increased abundance of creatine in the cells was due to elevated uptake from the microenvironment. Simultaneously, I found that T cells likewise accumulated creatine during effector function development and that deleting the creatine transporter SLC6A8 impaired T cell function by reducing cytokine production. In my project, I will focus on following aims: (i) to explore the impact of creatine metabolism in AML cells and T cells on the GVL effect; (ii) to test the potential of modulations in the hexosamine biosynthesis pathway and protein glycosylation for enhancement of the GVL effect; (iii) to determine the significance of oncogenic mutations and the type of AML treatment on metabolic competition between AML and T cells. I will achieve these objectives by using in vitro techniques and in vivo mouse models. The role of specific genes will be studied by CRISPR-Cas9-incuded knockdown and plasmid-mediated overexpression. Sample analysis will be performed by liquid-chromatography-mass spectrometry, RNA sequencing, flow cytometry and functional metabolic assays. The project will be supported by my host, Prof. Erika Pearce at the Johns Hopkins University School of Medicine, who will provide scientific expertise and the necessary technical equipment. This project aims to identify novel pharmacological strategies that target metabolic interactions between AML cells and T lymphocytes with the ultimate goal to boost the GVL effect and induce long-lasting AML remissions.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Erika Pearce, Ph.D.