Abstract
BackgroundT cells and cancer cells utilize glycolysis for proliferation. The hexokinase (1–4) family of enzymes catalyze the first step of glycolysis. Hexokinase 2 (HK2) is one of the most highly upregulated metabolic enzymes in both cancer and activated T cells. HK2 is required for the development and/or growth of cancer in several cancer models, but the necessity of HK2 in T cells is not fully understood. The clinical applicability of HK2 inhibition in cancer may be significantly limited by any potential negative effects of HK2 inhibition on T cells. Therefore, we investigated the necessity of HK2 for T cell function. In order to identify additional therapeutic cancer targets, we performed RNA-seq to compare in vivo proliferating T cells to T cell leukemia.MethodsHK2 was genetically ablated in mouse T cells using a floxed Hk2 allele crossed to CD4-Cre. CD4+ and CD8+ cells from mice were characterized metabolically and tested in vitro. T cell function in vivo was tested in a mouse model of colitis, Th2-mediated lung inflammation, and viral infection. Treg function was tested by crossing Hk2-floxed mice to FoxP3-Cre mice. Hematopoietic function was tested by deleting HK2 from bone marrow with Vav1-iCre. RNA-seq was used to compare T cells proliferating in response to virus with primary T-ALL leukemia induced with mutant Notch1 expression.ResultsWe unexpectedly report that HK2 is largely dispensable for in vitro T cell activation, proliferation, and differentiation. Loss of HK2 does not impair in vivo viral immunity and causes only a small impairment in the development of pathological inflammation. HK2 is not required for Treg function or hematopoiesis in vivo. One hundred sixty-seven metabolic genes were identified as being differentially expressed between T cells and leukemia.ConclusionsHK2 is a highly upregulated enzyme in cancer and in T cells. The requirement for HK2 in various cancer models has been described previously. Our finding that T cells are able to withstand the loss of HK2 indicates that HK2 may be a promising candidate for cancer therapy. Furthermore, we identify several other potential metabolic targets in T-ALL leukemia that could spare T cell function.
Highlights
T cells and cancer cells utilize glycolysis for proliferation
Hexokinase 2 (HK2) is dispensable for T cells in vitro To assess the necessity of HK2 for basic T cell function in vitro, we generated mice that have a conditional deletion of the Hk2 gene in T cells by crossing CD4-Cre mice with mice harboring a floxed Hk2 allele (Hk2fl/fl)
Glucose uptake capacity was measured by the amount of 2-DG taken up by cells. 2-DG uptake was unaffected by HK2 deficiency in CD4+ and CD8+ T cells (Fig. 1d)
Summary
T cells and cancer cells utilize glycolysis for proliferation. Hexokinase 2 (HK2) is one of the most highly upregulated metabolic enzymes in both cancer and activated T cells. T lymphocytes in the immune system and neoplastic cells in cancer are both highly proliferative cell types, relying on highly active metabolic pathways [1, 2]. One of the major side effects of chemotherapies which target proliferating cancer cells is immunosuppression. One common mechanism utilized by both cancer and activated T cells to support their proliferation is an upregulation of glycolysis to provide intermediates for macromolecule synthesis [3, 4]. Studies have shown that glucose metabolism is required for tumor growth in a variety of cancer models [12]. In the tumor microenvironment, evidence indicates that T cells and
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