Kay Kristen E, Lee Juyeun, Hong Ellen S, Beilis Julia, Dayal Sahil, Wesley Emily R, Mitchell Sofia, Wang Sabrina Z, Silver Daniel J, Volovetz Josephine, Johnson Sadie, McGraw Mary, Grabowski Matthew M, Lu Tianyao, Freytag Lutz, Narayana Vinod, Freytag Saskia, Best Sarah A, Whittle James R, Wang Zeneng, Reizes Ofer, Yu Jennifer S, Hazen Stanley L, Brown J Mark, Bayik Defne, Lathia Justin D
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Cleveland Clinic Lerner College of Medicine; and.
J Clin Invest. 2024 Nov 19;135(2):e177824. doi: 10.1172/JCI177824.
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.
胶质母细胞瘤（GBM）微环境富含免疫抑制因子，这些因子会强烈干扰细胞毒性T淋巴细胞的功能。癌细胞可直接影响免疫系统，但驱动这些相互作用的机制尚不完全清楚。在此，我们证明多胺代谢物亚精胺（SPD）在GBM肿瘤微环境中升高。在临床前小鼠模型中，外源性给予SPD通过降低CD8 + T细胞频率和细胞毒性功能，以免疫依赖的方式驱动肿瘤侵袭性。鸟氨酸脱羧酶是SPD合成中的限速酶，敲低该酶不会影响体外癌细胞生长，但会延长生存期。此外，与预后不良的患者相比，预后较好的GBM患者体内的SPD显著降低。我们的结果表明，SPD作为一种癌细胞衍生的代谢物，通过减少CD8 + T细胞数量和功能来驱动肿瘤进展。
