Tmic-35. tumor cell-derived spermidine accelerates glioblastoma progression via lymphocyte depletion

Abstract Therapeutic resistance in glioblastoma (GBM) is partly due to a highly immunosuppressive environment resulting in ineffective anti-tumor immune response. This likely underlies the lack of success of immunotherapies that are successful in other cancers; novel ways to target this environment are needed. Naturally occurring polyamines (PAs) have been identified as a putative therapeutic target in other cancers based on their increased presence and correlation to poorer prognosis. Under normal conditions, spermidine (SPD) – a member of the PA family – is critical for cell growth. While PAs are increased in GBM patients, little is known about their impact on GBM growth. In syngeneic immunocompetent mouse glioma models, mass spectrometry revealed that SPD increases in the tumor microenvironment and circulation as compared to non-tumor-bearing mice. We treated the same models with exogenous SPD, which significantly decreased survival. However, in immunocompromised mice, no survival difference was observed, suggesting SPD drives GBM progression through immune interaction. Immune profiling the mouse models treated with SPD showed peripheral reduction of CD4+ and CD8+ T cells. Due to the observed T cell changes, we repeated the exogenous SPD paradigm in RAG1 knockout mice that do not have circulating B/ T cells. Similar to NSG mice, we see no survival difference, indicating that SPD drives GBM by affecting lymphoid cells. To investigate the origin of SPD in our models, we knocked down the rate limiting enzyme of the PA biosynthesis pathway in glioma cells in immunocompetent mice. Mice implanted with knockdown cells showed a robust survival extension, suggesting that tumor cells produce SPD which affects the tumor microenvironment. Ongoing studies are evaluating uptake from the environment on the progression of GBM using pharmacological inhibitors. Understanding the interactions of PAs and the immune response as a whole will allow us to alter the environment to enhance immunotherapeutic efficacy.