Rebalancing TGF-13/PGE2 breaks RT-induced immuno suppressive barriers by enhancing tumor-infiltrated dendritic cell homing
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES(2024)
Abstract
A better understanding of how tumor microenvironments shape immune responses after radiotherapy (RT) is required to improve patient outcomes. This study focuses on the observation that dendritic cells (DCs) infiltrating irradiated cervical tumors are retained in transforming growth factor (TGF)-13-abundant regions. We report that TGF-13 secretion from cervical cancer cells was increased by irradiation in a dose-dependent manner and that this significantly suppressed the expression of allostimulatory markers and Th1 cytokines in DCs. To investigate further, we blocked the TGF-13 signal in DCs and observed that RT had a dose-dependent immune-promoting effect, improving DC maturation. This suggested that proinflammatory mediators may also be induced by RT, but their effects were being counteracted by the simultaneously increased levels of TGF-13. Prostaglandin E2 (PGE2), a proinflammatory molecule, was shown to be one such mediator. Adjusting the TGF-13/PGE2 ratio by inhibiting TGF-13 rebooted RT-induced DC cytoskeletal organization by stimulating myosin light chain (MLC) phosphorylation. Consequently, the homing of intra-tumorally infiltrated DCs to tumor-draining lymph nodes was enhanced, leading to the induction of more robust cytotoxic T cells. Ultimately, rebalancing the TGF-13/PGE2 ratio amplified the therapeutic effects of RT, resulting in increased intra-tumoral infiltration and activation of CD8+ T cells, and improved tumor control and overall survival rate in mice. DC depletion experiments verified that the improvement in tumor control is directly correlated with the involvement of DCs via the PGE2-MLC pathway. This study emphasizes the importance of maintaining a balanced cytokine environment during RT, particularly hypofractionated RT; and it is advisable to block TGF-13 while preserving PGE2 in the tumor microenvironment in order to better stimulate DC homing and DC-T priming.
MoreTranslated text
Key words
dendritic cell,radiotherapy,cervical cancer,TGF-beta
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined