Polyamine Immunometabolism: Central Regulators of Inflammation, Cancer and Autoimmunity

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.

Keywords: autoimmunity; cancer; myeloid cells; polyamines.

Figure 1

Overall role of polyamines in inflammatory processes of immune subsets. Sparked by three high-impact publications, the role of polyamine on CD4+ T-cell physiology is highly controversial (A). In the first publication, (i) blockade of polyamine synthesis led to unstable lineage fidelity, resulting in uncontrolled inflammation. In the other publications, (ii) polyamine blockade led to the amelioration of experimental autoimmune encephalomyelitis (EAE) by preventing inflammatory Th17 pathogenesis and inducing a regulatory T-cell phenotype. In the only study to date that directly examines polyamine function in CD8+ T-cells, the authors found thorough CRISPR screening that the deletion of ODC1 led to enhanced cytotoxicity and the degranulation of T-cells (B). In myeloid lineage, cells and microglia polyamines are uniformly associated with inhibition of inflammation and autoimmune phenotypes (C). In dendritic cells (DCs), a metabolic positive feedforward loop instigated by IFN-y and/or TGF-b results in a tolerogenic phenotype (D). Blockade of many aspects of this pathway in DCs leads to increased autoimmune inflammation. Figure created with BioRender.com.

Figure 2

Myeloid-linked mechanisms by which polyamines promote immunosuppression in cancer. While the mechanisms are still being uncovered, there are several potential mechanisms for why polyamine accumulation in myeloid cells is immunosuppressive (A). One hypothesis is that the propensity of alternatively activated macrophages to consume arginine, the precursor to polyamines, deplete arginine from the inflammatory microenvironment sequestering it from T-cells that need it for activation/function (B). Another proposed mechanism is that polyamine generation by myeloid cells directly feeds tumors as they actively take-up polyamines (C). Another mechanistic study indicated that polyamines drive mitochondrial gene expression and promote the metabolic phenotype associated with alternatively activated macrophages (D). We have recently shown that polyamine can be used as a mechanism to buffer intracellular pH to allow for the survival and function of myeloid cells in brain tumors (E). Despite the growing list of mechanisms by which polyamines promote immune suppression in myeloid cells, much of the biology is still yet to be determined. Figure created with BioRender.com.

Figure 3

Polyamines maintain the delicate balance of immunity and tolerance by myeloid cells. In typical scenarios, inflammation is a transient process, by which immunogenic signals eliciting a response are cleared. In order to slow down these processes, the immune system has several internal checkpoints meant to prevent uncontrolled immunity from occurring. These processes occur over time, with an initial wave of inflammation followed by upregulation of checkpoints designed to put the brakes on the immune system (A). For myeloid cells, this switch to a pro-resolution phenotype is associated with arginase-1 metabolism, ODC1 activity, and ultimately polyamine synthesis. This response is stimulated by the phagocytosis of apoptotic bodies, which act as a source for arginine and nucleotides for these cells to suppress and proliferate, respectively (B). It is likely that tumors take advantage of this process as the tumor continues to grow by providing chronic inflammatory signals to recruit myeloid cells and then providing apoptotic bodies (and other immunomodulatory signals) to promote their M2-like or pro-resolving phenotype (C). From the perspective of polyamines, they increase as the cell goes from an inflammatory phenotype to a pro-resolution or immunosuppressive phenotype. Thus, a deficiency in polyamine levels may perpetuate inflammation, while conversely, excessive levels promote tumorigenesis and immunosuppression. Figure created with BioRender.com.