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.

Lactate secreted by cervical cancer cells modulates macrophage phenotype

“…Mϕs play an important role in many solid tumor progression and immune evasion mechanisms . This happens due to the immunomodulatory properties of the tumor microenvironment.…”

“…The later includes adenosine, produced from ATP through the activity of CD39 and CD73 expressed by either tumor or stroma cells, and tryptophan metabolites, as kynurenine, generated through the activity of enzymes as indoleamine‐ 2,3 dioxygenase . Lactate, a by‐product of tumor cell metabolism, secreted to the extracellular environment, exerts an immunomodulatory role in several immune cells . In this work, we evaluated the effect of lactate secreted by cervical cancer cells in the modulation of human Mϕs phenotype.…”

“…M s play an important role in many solid tumor progression and immune evasion mechanisms. 38 This happens due to the immunomodulatory properties of the tumor microenvironment. Soluble factors secreted by tumor cells, including cytokines, lipid mediators and metabolites can modulate M phenotype.…”

“…40 Lactate, a by-product of tumor cell metabolism, secreted to the extracellular environment, exerts an immunomodulatory role in several immune cells. 38 In this work, we tumor cell senescence. 42,43 48 It would be interesting to inhibit the expression of these receptors to be able to access their role in the phenomenon we are describing in this work.…”

Autofluorescence imaging of 3D tumor-macrophage microscale cultures resolves spatial and temporal dynamics of macrophage metabolism

“…This increases the production of the metabolic co-enzyme, NADH, via glycolysis and sustains the viability of M1-like macrophages within tumors [14][15][16] . Conversely, elevated fatty acid oxidation and oxidative phosphorylation in M2-like macrophages support angiogenesis and tumor growth [14][15][16][17][18][19] . Here, fatty acid oxidation generates acetyl-CoA and NADH, driving downstream oxidative phosphorylation 17,19 .…”