Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment

Abstract

Cytotoxic T lymphocytes and NK cells play an important role in eliminating malignant tumor cells and the number and activity of tumor-infiltrating T cells represent a good marker for tumor prognosis. Based on these findings, immunotherapy, e.g., checkpoint blockade, has received considerable attention during the last couple of years. However, for the majority of patients, immune control of their tumors is gray theory as malignant cells use effective mechanisms to outsmart the immune system. Increasing evidence suggests that changes in tumor metabolism not only ensure an effective energy supply and generation of building blocks for tumor growth but also contribute to inhibition of the antitumor response. Immunosuppression in the tumor microenvironment is often based on the mutual metabolic requirements of immune cells and tumor cells. Cytotoxic T and NK cell activation leads to an increased demand for glucose and amino acids, a well-known feature shown by tumor cells. These close metabolic interdependencies result in metabolic competition, limiting the proliferation, and effector functions of tumor-specific immune cells. Moreover, not only nutrient restriction but also tumor-driven shifts in metabolite abundance and accumulation of metabolic waste products (e.g., lactate) lead to local immunosuppression, thereby facilitating tumor progression and metastasis. In this review, we describe the metabolic interplay between immune cells and tumor cells and discuss tumor cell metabolism as a target structure for cancer therapy. Metabolic (re)education of tumor cells is not only an approach to kill tumor cells directly but could overcome metabolic immunosuppression in the tumor microenvironment and thereby facilitate immunotherapy.

Keywords: cytokines; glycolysis and oxidative phosphorylation; immune cell functions; immune cell metabolism; immune escape; tumor metabolism.

Figure 1

Metabolic hallmarks of tumor cells and the interplay between tumor cells and immune cells. Tumor cells exhibit high expression of glucose transporteres (GLUT), lactate dehydrogenase (LDH), cyclooxygenase (COX), arginase (ARG), indolamine 2,3-dioxygenase (IDO), glutaminase (GLS), and oxidative phosphorylation (OXPHOS). As a consequence, glucose and the amino acids arginine, tryptophan, and glutamine are depleted from the tumor microenvironment and nutrient restriction leads to an anergic status of antitumoral cytotoxic T cells. In addition, accelerated glycolysis by tumor cells results in lactate production and secretion via monocarboxylate-transporters (MCT). Lactate and other metabolites, such as glutamate, prostaglandins (PGE2), and kynurenines, affect immune cells. Overexpression of the ecto-5′-nucleotidase (CD73) leads to adenosine formation; loss of methylthioadenosine phosphorylase (MTAP) results in methylthioadenosine (MTA) accumulation in the tumor environment.

Figure 2

Metabolic target structures in tumor cells and possible inhibitors. Glucose metabolism is an attractive target for cancer therapy. Rapamycin (Rapa) inhibits the mammalian target of rapamycin pathway and glycolysis. 2-Deoxyglucose (2-DG) and bromopyruvate (3-BP) target hexokinase II, the rate-limiting enzyme of the glycolytic pathway. The lactate dehydrogenase (LDH) inhibitors FX11 and galloflavin block lactate production. Diclofenac (Diclo), lenalidomide, and AZD3965 limit lactate secretion via blocking lactate transporters (MCT). Oxidative phosphorylation (OXPHOS) is diminished by metformin and sorafenib. CB-389 is a glutaminase (GLS) inhibitor elevating glutamine levels while concomittantly decreasing glutamate. CB-1158 inhibits arginase (ARG) and thereby increases arginine levels, whereas ADI-PEG20 depletes arginine. Antibodies against the ecto-5′-nucleotidase (CD73) inhibit adenosine formation. Non-steroidal anti-inflammatory drugs (NSAIDs) block cyclooxygenase (COX) activity and decrease prostaglandin (PGE2) production. Indolamine 2,3-dioxygenase (IDO) can be targeted by Epacadostat and 1-methyl-tryptophan (1-MT), which results in lower kynurenine secretion and higher tryptophan levels.