Abstract
The role of tumor microenvironment (TME)-associated inadequate protein modification and trafficking due to insufficiency in Golgi function, leading to Golgi stress, in the regulation of T cell function is largely unknown. Here, we show that disruption of Golgi architecture under TME stress, identified by the decreased expression of GM130, was reverted upon treatment with hydrogen sulfide (HS) donor GYY4137 or overexpressing cystathionine β-synthase (CBS), an enzyme involved in the biosynthesis of endogenous HS, which also promoted stemness, antioxidant capacity, and increased protein translation, mediated in part by endoplasmic reticulum-Golgi shuttling of Peroxiredoxin-4. In in vivo models of melanoma and lymphoma, antitumor T cells conditioned ex vivo with exogenous HS or overexpressing CBS demonstrated superior tumor control upon adoptive transfer. Further, T cells with high Golgi content exhibited unique metabolic and glycation signatures with enhanced antitumor capacity. These data suggest that strategies to mitigate Golgi network stress or using Golgitumor-reactive T cells can improve tumor control upon adoptive transfer.
Overview
- The study investigates the role of tumor microenvironment (TME)-associated inadequate protein modification and trafficking due to insufficiency in Golgi function, leading to Golgi stress, in the regulation of T cell function. The study aims to understand the mechanisms underlying Golgi stress and its impact on T cell function and to identify potential therapeutic strategies to mitigate Golgi network stress or use Golgitumor-reactive T cells to improve tumor control upon adoptive transfer. The methodology used for the experiment includes in vitro and in vivo models of melanoma and lymphoma, ex vivo conditioning of T cells with exogenous hydrogen sulfide (HS) or overexpression of cystathionine β-synthase (CBS), and analysis of Golgi stress, stemness, antioxidant capacity, protein translation, metabolic and glycation signatures, and antitumor capacity. The primary objective of the study is to identify potential therapeutic strategies to improve tumor control upon adoptive transfer of T cells.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions or interventions, including the disruption of Golgi architecture under TME stress, identified by the decreased expression of GM130, and the reversion of this disruption upon treatment with hydrogen sulfide (HS) donor GYY4137 or overexpressing cystathionine β-synthase (CBS), an enzyme involved in the biosynthesis of endogenous HS. The study identifies that T cells with high Golgi content exhibit unique metabolic and glycation signatures with enhanced antitumor capacity. The key findings of the study suggest that strategies to mitigate Golgi network stress or using Golgitumor-reactive T cells can improve tumor control upon adoptive transfer.
Implications and Future Directions
- The study's findings suggest that Golgi stress plays a crucial role in the regulation of T cell function and that strategies to mitigate Golgi network stress or use Golgitumor-reactive T cells can improve tumor control upon adoptive transfer. The study identifies potential therapeutic strategies to mitigate Golgi network stress or use Golgitumor-reactive T cells to improve tumor control. However, the study has limitations, such as the use of in vitro and in vivo models, which may not fully capture the complexity of the TME. Future research directions could include the development of more advanced in vivo models to better understand the role of Golgi stress in the TME and the development of more targeted therapies to mitigate Golgi network stress or use Golgitumor-reactive T cells to improve tumor control.