Abstract
Polyamines are ubiquitous, amine-rich molecules with diverse processes in biology. Recent work has highlighted that polyamines exert profound roles on the mammalian immune system, particularly inflammation and cancer. The mechanisms by which they control immunity are still being described. In the context of inflammation and autoimmunity, polyamine levels inversely correlate to autoimmune phenotypes, with lower polyamine levels associated with higher inflammatory responses. Conversely, in the context of cancer, polyamines and polyamine biosynthetic genes positively correlate with the severity of malignancy. Blockade of polyamine metabolism in cancer results in reduced tumor growth, and the effects appear to be mediated by an increase in T-cell infiltration and a pro-inflammatory phenotype of macrophages. These studies suggest that polyamine depletion leads to inflammation and that polyamine enrichment potentiates myeloid cell immune suppression. Indeed, combinatorial treatment with polyamine blockade and immunotherapy has shown efficacy in pre-clinical models of cancer. Considering the efficacy of immunotherapies is linked to autoimmune sequelae in humans, termed immune-adverse related events (iAREs), this suggests that polyamine levels may govern the inflammatory response to immunotherapies. This review proposes that polyamine metabolism acts to balance autoimmune inflammation and anti-tumor immunity and that polyamine levels can be used to monitor immune responses and responsiveness to immunotherapy.
Highlights
Polyamines are highly charged aliphatic polycations present in all living organisms.Polyamines are so fundamental to mammalian biology that depletion leads to total arrest in translation and proliferation of all cells [1]
The fact that CD4 deficiency of polyamine metabolism leads to uncontrolled inflammation in the gut [33], whereas the same deficiency inhibits CNSinflammatory pathology, which suggests that polyamine metabolism may play divergent roles in Th-function depending on the location of the disease
Even less is known about how polyamine levels may act as a proxy for understanding the immunological state of a disease or therapeutic response
Summary
Polyamines are highly charged aliphatic polycations present in all living organisms. Polyamines are so fundamental to mammalian biology that depletion leads to total arrest in translation and proliferation of all cells [1]. Polyamines facilitate proliferative processes by modifying the chromosomal structure, influencing protein/DNA interactions, and likely through other mechanisms that are still unknown [2] Another role in proliferation for polyamines is as a substrate in the hypusination of the transcription factor EIF5a. EIF5a is an ancient transcription factor found across all archaea and eukaryotes, and the only polyamine-covalent modification described to date [3], key in regulating cellular translation [4,5]. They play an important role in the apoptotic processes within a cell. Recent studies have indicated that polyamines can promote longevity and cognitive function [10–12] In these studies, the authors demonstrate spermidine administration from exogenous sources, including the diet [12], leads to enhanced neurocognitive function through the induction of protective autophagy and increased mitochondrial function. We will discuss the current landscape of polyamines in autoimmunity, immune suppression, and how immunotherapies may regulate these processes
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