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.

No abstract

Immunotherapy has revolutionized cancer treatment but has yet to be translated into brain tumors. Studies in other solid tumors suggest a central role of B-cell immunity in driving immune-checkpoint-blockade efficacy. Using single-cell and single-nuclei transcriptomics of human glioblastoma and melanoma brain metastasis, we found that tumor-associated B-cells have high expression of checkpoint molecules, known to block B-cell-receptor downstream effector function such as plasmablast differentiation and antigen-presentation. We also identified TGFβ-1/TGFβ receptor-2 interaction as a crucial modulator of B-cell suppression. Treatment of glioblastoma patients with pembrolizumab induced expression of B-cell checkpoint molecules and TGFβ-receptor-2. Abrogation of TGFβ using different conditional knockouts expanded germinal-center-like intratumoral B-cells, enhancing immune-checkpoint-blockade efficacy. Finally, blocking αVβ8 integrin (which controls the release of active TGFβ) and PD-1 significantly increased B-cell-dependent animal survival and immunological memory. Our study highlights the importance of intratumoral B-cell immunity and a remodeled approach to boost the effects of immunotherapy against brain tumors.