The role of polyamine metabolism in remodeling immune responses and blocking therapy within the tumor immune microenvironment

Abstract

The study of metabolism provides important information for understanding the biological basis of cancer cells and the defects of cancer treatment. Disorders of polyamine metabolism is a common metabolic change in cancer. With the deepening of understanding of polyamine metabolism, including molecular functions and changes in cancer, polyamine metabolism as a new anti-cancer strategy has become the focus of attention. There are many kinds of polyamine biosynthesis inhibitors and transport inhibitors, but not many drugs have been put into clinical application. Recent evidence shows that polyamine metabolism plays essential roles in remodeling the tumor immune microenvironment (TIME), particularly treatment of DFMO, an inhibitor of ODC, alters the immune cell population in the tumor microenvironment. Tumor immunosuppression is a major problem in cancer treatment. More and more studies have shown that the immunosuppressive effect of polyamines can help cancer cells to evade immune surveillance and promote tumor development and progression. Therefore, targeting polyamine metabolic pathways is expected to become a new avenue for immunotherapy for cancer.

Keywords: T cell; adaptive immune; immunotherapy; innate immune; metabolism; polyamine; tumor immune microenvironment.

Figure 1

The biological function of polyamines. Polyamines have multiple roles in cells, including regulation of gene expression, RNA structure, protein synthesis, ion channel flux, and autophagy. Polyamines are required for growth and play important roles in a variety of physiological processes, including immunity, aging, hair growth, and wound healing.

Figure 2

The polyamine metabolic pathway and transport way. Polyamine biosynthesis involves the conversion of ornithine to putrescine by ornithine decarboxylase (ODC), followed by the formation of spermidine via spermidine synthase (SRM) and decarboxylated s-adenosylmethionine (dcSAM, formed by AMD1). The aminopropyl fragment required for putrescine to produce spermidine was provided by dcSAM. In a similar manner, spermine is produced from the conversion of spermidine by spermine synthase (SMS) and AMD1. The polyamine catabolism process occurs through the action of amine oxidase, mainly polyamine oxidase (PAOX) and spermine oxidase (SMOX). PAOX and SMOX can generate a large amount of reactive oxygen species (ROS) during the process of decomposing polyamines, causing oxidative damage. Currently, three models of polyamine transport systems have been proposed. Although the molecules involved in the polyamine transport system have not been fully recognized, it is known that the polyamine transport system is energy dependent and substrate selective. ODC antienzymes (AZs) and antizyme inhibitors (AZINs) also play important roles in polyamine transport. ODC monomers have a higher affinity for AZs. When the intracellular polyamine concentration is high, AZs binds to ODC monomers, preventing ODC activity and promoting the binding of ODC monomers to the 26S proteasome for degradation in a ubiquitin (Ub)-independent manner (only AZ1 induces ODC degradation). However, the binding of AZs to ODC can be blocked by AZINs.

Figure 3

The role of polyamines in both innate and adaptive immune responses in cancer Polyamines and their key enzymes can reshape the tumor immune microenvironment through a variety of transcription factors or cytokines, even have dual roles. The polyamine-eIF5A-hypusine axis regulates macrophage polarization, especially polyamines tend to promote the polarization of M2-type macrophages. Polyamines also negatively regulated the functions of DC cells, NKT cells, CD8+ TILs and Th1 cells, and positively regulated the functions of Treg cells. For NK cells, polyamines are a double-edged sword. In fact, the tumor immune microenvironment is mutually influenced and restricted by a variety of factors. The regulation of polyamines in regulating the function of immune cells is not absolute, which will change according to the changes of tumor immune microenvironment.