Li Mei, Chen Yi-Ling, Pearce Lilly M, Hammett Amy M, Sharma Falak H, Miller Derick S, Chen Kuan-Hui E
Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA.
Department of Electronic Engineering, National Kaohsiung University of Science and Technology, Kaohsiung 80778, Taiwan.
Int J Mol Sci. 2025 May 8;26(10):4482. doi: 10.3390/ijms26104482.
Asymmetric dimethylarginine (ADMA), an endogenous methylated amino acid, has been implicated in tumor progression; however, its influence on tumor immunity, particularly dendritic cell (DC) function and antigen presentation, remains unclear. In this study, we examined the effects of ADMA on tumor antigen uptake, processing, and presentation in DCs using the murine dendritic cell line DC2.4 as a model. Our results reveal that ADMA treatment significantly reduces the phagocytic uptake of tumor antigens derived from EO771 and Py230 breast cancer cell lysates. Additionally, ADMA exposure leads to a marked downregulation of key genes involved in antigen processing and presentation, including , , , , , and . This suppression at the transcriptional level corresponds with decreased surface protein expression of MHC I, MHC II, and CD80, as confirmed by flow cytometry. Furthermore, ADMA-treated DC2.4 cells exhibit impaired tumor antigen presentation on their surface. Consequently, these functional impairments result in a diminished capacity to activate CD4 T cells, as evidenced by a 41.18% decrease in CD25 expression and a 30.28% reduction in IFN-γ secretion. Similarly, CD8 T cell activation is compromised, as indicated by a 32.26% decrease in IFN-γ production, although CD25 expression remains unaffected. Collectively, our findings identify ADMA as a potential immunosuppressive factor that disrupts antigen uptake, processing, and presentation in DCs, thereby modulating T cell activation. These insights suggest a potential mechanism through which ADMA may contribute to immune evasion within the tumor microenvironment.
不对称二甲基精氨酸（ADMA）是一种内源性甲基化氨基酸，与肿瘤进展有关；然而，其对肿瘤免疫的影响，特别是对树突状细胞（DC）功能和抗原呈递的影响仍不清楚。在本研究中，我们以小鼠树突状细胞系DC2.4为模型，研究了ADMA对DC中肿瘤抗原摄取、加工和呈递的影响。我们的结果显示，ADMA处理显著降低了源自EO771和Py230乳腺癌细胞裂解物的肿瘤抗原的吞噬摄取。此外，ADMA暴露导致参与抗原加工和呈递的关键基因显著下调，包括 、 、 、 、 和 。如通过流式细胞术所证实的，转录水平的这种抑制与MHC I、MHC II和CD80表面蛋白表达的降低相对应。此外，经ADMA处理的DC2.4细胞在其表面呈现肿瘤抗原的能力受损。因此，这些功能障碍导致激活CD4 T细胞的能力减弱，CD25表达降低41.18%和IFN-γ分泌减少30.28%证明了这一点。同样，CD8 T细胞激活也受到损害，IFN-γ产生减少32.26%表明了这一点，尽管CD25表达未受影响。总体而言，我们的研究结果确定ADMA是一种潜在的免疫抑制因子，它破坏DC中的抗原摄取、加工和呈递，从而调节T细胞激活。这些见解提示了ADMA可能在肿瘤微环境中促成免疫逃逸的潜在机制。
