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

Kay, KE; Lee, J; Hong, ES; Beilis, J; Dayal, S; Wesley, ER; Mitchell, S; Wang, SZ; Silver, DJ; Volovetz, J; Johnson, S; McGraw, M; Grabowski, MM; Lu, T; Freytag, L; Narayana, V; Freytag, S; Best, SA; Whittle, JR; Wang, Z; Reizes, O; Yu, JS; Hazen, SL; Brown, JM; Bayik, D; Lathia, JD

Author(s): Kay, KE; Lee, J; Hong, ES; Beilis, J; Dayal, S; Wesley, ER; Mitchell, S; Wang, SZ; Silver, DJ; Volovetz, J; Johnson, S; McGraw, M; Grabowski, MM; Lu, T; Freytag, L; Narayana, V; Freytag, S; Best, SA; Whittle, JR; Wang, Z; Reizes, O; Yu, JS; Hazen, SL; Brown, JM; Bayik, D; Lathia, JD;
Details: Publication Year 2024-11-19,Volume 135,Issue #2,Page e177824
Journal Title: Journal of Clinical Investigation
Abstract: The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly affect the immune system, but the mechanisms driving these interactions are not completely clear. Here, we demonstrate that the polyamine metabolite spermidine (SPD) was elevated in the GBM tumor microenvironment. Exogenous administration of SPD drove tumor aggressiveness in an immune-dependent manner in preclinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in SPD synthesis, did not affect cancer cell growth in vitro but did result in extended survival. Furthermore, patients with GBM with a more favorable outcome had a significant reduction in SPD compared with patients with a poor prognosis. Our results demonstrate that SPD functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+ T cell numbers and function.
Publisher: ASCI
Keywords: *Spermidine/pharmacology; Animals; Humans; *Glioblastoma/immunology/pathology/drug therapy/metabolism; *Tumor Microenvironment/immunology/drug effects; Mice; *CD8-Positive T-Lymphocytes/immunology; Cell Line, Tumor; Female; Brain Neoplasms/immunology/pathology/drug therapy/metabolism; Male; Ornithine Decarboxylase/metabolism/genetics/immunology; Adaptive immunity; Brain cancer; Immunology; Oncology; Polyamines
Research Division(s): Personalised Oncology
PubMed ID: 39561012
Publisher's Version: https://doi.org/10.1172/JCI177824
Open Access at Publisher's Site: https://doi.org/10.1172/JCI177824
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-01-21 10:07:47

Last Modified: 2025-01-21 11:03:01