Tejero Joanne D, Hesterberg Rebecca S, Drapela Stanislav, Ilter Didem, Raizada Devesh, Lazure Felicia, Kashfi Hossein, Liu Min, Silvane Leonardo, Avram Dorina, Fernández-García Juan, Asara John M, Fendt Sarah-Maria, Cleveland John L, Gomes Ana P
Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
Department of Molecular Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, 33612, USA.
Oncogene. 2025 Jan;44(2):105-114. doi: 10.1038/s41388-024-03191-1. Epub 2024 Oct 29.
Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8 T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that lead to increased systemic levels of MMA. Thus, we hypothesized that increased circulatory levels of MMA would lead to a suppression of CD8 T cell immunity. Treatment of primary CD8 T cells with MMA induced a dysfunctional phenotype characterized by robust immunosuppressive transcriptional reprogramming and marked increases in the expression of the exhaustion regulator, TOX. Accordingly, MMA treatment upregulated exhaustion markers in CD8 T cells and decreased their effector functions, which drove the suppression of anti-tumor immunity in vitro and in vivo. Mechanistically, MMA-induced CD8 T cell exhaustion was associated with a suppression of NADH-regenerating reactions in the TCA cycle and concomitant defects in mitochondrial function. Thus, MMA has immunomodulatory roles, thereby highlighting MMA as an important link between aging, immune dysfunction, and cancer.
丙酸代谢的副产物甲基丙二酸（MMA）的全身水平会随着年龄增长而升高，且MMA通过对肿瘤细胞的直接作用促进肿瘤进展。然而，MMA在调节肿瘤生态系统中的作用仍有待研究。CD8 T细胞作为关键的抗肿瘤免疫细胞，其增殖和功能会随着年龄增长以及在维生素B12缺乏的情况下而下降，这两种情况是导致全身MMA水平升高的最明确的条件。因此，我们推测循环中MMA水平升高会导致CD8 T细胞免疫受到抑制。用MMA处理原代CD8 T细胞会诱导出一种功能失调的表型，其特征是强大的免疫抑制转录重编程以及耗竭调节因子TOX的表达显著增加。相应地，MMA处理上调了CD8 T细胞中的耗竭标志物并降低了它们的效应功能，这在体外和体内都导致了抗肿瘤免疫的抑制。从机制上讲，MMA诱导的CD8 T细胞耗竭与三羧酸循环中NADH再生反应的抑制以及线粒体功能的伴随缺陷有关。因此，MMA具有免疫调节作用，从而突出了MMA作为衰老、免疫功能障碍和癌症之间的重要联系。
