The cancer metabolic reprogramming and immune response

Abstract

The overlapping metabolic reprogramming of cancer and immune cells is a putative determinant of the antitumor immune response in cancer. Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of antitumor immune response through both the release of metabolites and affecting the expression of immune molecules, such as lactate, PGE₂, arginine, etc. Actually, this energetic interplay between tumor and immune cells leads to metabolic competition in the tumor ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function. More interestingly, metabolic reprogramming is also indispensable in the process of maintaining self and body homeostasis by various types of immune cells. At present, more and more studies pointed out that immune cell would undergo metabolic reprogramming during the process of proliferation, differentiation, and execution of effector functions, which is essential to the immune response. Herein, we discuss how metabolic reprogramming of cancer cells and immune cells regulate antitumor immune response and the possible approaches to targeting metabolic pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments between immunotherapy and metabolic intervening that could be used to better unleash the potential of anticancer therapies.

Keywords: Immune checkpoint…; Immunity; Metabolic reprogramming; Oxysterols; TIL; TME.

Fig. 1

Regulation of glucose metabolism in cancer cells. Glucose metabolism mainly contains glycolysis and TCA cycle in the mitochondrion. These pathways are generally altered in tumor cells compared to normal cells

Fig. 2

The nutritional competition between tumor cells and immune cells inside tumors. The competition-caused deficiency of glucose, glutamine, and fatty acids and a couple of amino acids are known to affect the function of immune cells, including Treg, macrophages, dendritic cell, NK cells and so on

Fig. 3

The regulation of metabolites produced by tumor cells in immune cells The metabolites are known regulators of immune cell function, such as lactate, fatty acid, PGE₂ and arginine, etc. As a consequence, the accumulation of extracellular lactate and the amino acids arginine, tryptophan, and glutamine in the tumor environment could affect the proliferation, function and differentiation of immune cells, and the production of cytokines. The glucose-deprived, lactic acid-enriched TME impairs T cell and NK cell function and thus antitumor immune responses and polarizes tumor-associated macrophages (TAMs) towards a generally pro-tumor, M2-like phenotype. Competition for amino acids, including arginine and tryptophan, between immune cells and tumor cells can also suppress antitumor immunity. The availability and usage of fatty acids in immune cells within the TME are also influenced by competition with tumor cells. Notably, a high rate of cholesterol esterification in the tumor can impair immune responses and, therefore, disruption of cholesterol esterification in order to increase the concentration of cholesterol in the plasma membranes of immune cells might increase their proliferation and improve their effector function. The generation of prostaglandin E2 (PGE₂), by tumor cells and other immunomodulatory cells is also implicated in the suppression of antitumor responses

Fig. 4

The regulation of metabolic pathway in immune cells. a The activation of mTORC1 induced by various factors (cytokines, glucose and oxygen, etc.) up-regulates PD-L1 expression, and inhibits the Treg cells, NK cells and T cell infiltration. In addition, the growth factors-induced mTORC2 activation could increase AKT expression and affect the glutamine metabolism, ultimately causing the ICIs (immune checkpoint inhibitors) resistance and promote the cancer growth and development. b AMPK activation enhances the uptake of fatty acids and glucose via FAT/CD36 and GLUT4 respectively. Meanwhile, the activation of AMPK increases the fatty acids oxidation and oxidative phosphorylation in mitochondria to elevate the intracellular ATP level. Ultimately, these alterations commonly affect the functions of immune cells, such as inhibiting Treg cells differentiation and function, decreasing CD4⁺ T cell activity, inducing MDSC cells (marrow-derived suppressor cells) and elevating the secretion of IL-17, IL-1, and IL-18, which ultimately lead to the immunosuppression

Fig. 5

Cross-regulation of immunometabolic signaling pathways in T cell. Under hypoxia conditions, HIF-1α signaling activates anabolism-associated programs, such as glycolysis and fatty acid synthesis; however, these mechanisms require additional investigation in primary T cells. AMPK directly inhibits HIF-1α. During activation and/or replete nutrient conditions, PI3K-AKT and Ras signaling promotes glycolysis, fatty acid oxidation. PI3K-Akt can reportedly inhibit the AMPK, but this regulation is not yet reported to occur in T cells

Fig. 6

Metabolic hallmarks of immune cells and the interplay between immune cells and immune cells. Immune 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), etc. As a consequence, glucose and the amino acids arginine, tryptophan, and glutamine are depleted from the immune microenvironment and nutrient restriction leads to an anergic status of anti-tumoral cytotoxic T cells. In addition, accelerated glycolysis by some immune cells results in lactate production and secretion via monocarboxylate-transporters (MCTs). Lactate and other metabolites, such as glutamate, prostaglandins (PGE₂), kynurenines, cholesterol and R-5-P, affect immune cells