Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition

Kay, K.; Lee, J.; Hong, E. S.; Beilis, J.; Dayal, S.; Wesley, E. R.; Mitchell, S.; Wang, S. Z.; Silver, D. J.; Volovetz, J.; Johnson, S.; McGraw, M.; Grabowski, M. M.; Lu, T.; Freytag, L.; Narayana, V.; Freytag, S.; Best, S. A.; Whittle, J. R.; Wang, Z.; Reizes, O.; Yu, J. S.; Hazen, S. L.; Brown, J. M.; Bayik, D.; Lathia, J.

doi:10.1101/2023.11.14.567048

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bioRxiv · 10.1101/2023.11.14.567048

Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition

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Abstract

The glioblastoma microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine is elevated in the glioblastoma tumor microenvironment. Exogenous administration of spermidine drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and phenotype. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+T cell number and function.

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Kay, K., Lee, J., Hong, E. S., Beilis, J., Dayal, S., Wesley, E. R., Mitchell, S., Wang, S. Z., Silver, D. J., Volovetz, J., Johnson, S., McGraw, M., Grabowski, M. M., Lu, T., Freytag, L., Narayana, V., Freytag, S., Best, S. A., Whittle, J. R., Wang, Z., Reizes, O., Yu, J. S., Hazen, S. L., Brown, J. M., Bayik, D., Lathia, J.. 2023-11-16. Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition. https://doi.org/10.1101/2023.11.14.567048

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