Abstract 41P
Background
The tumor microenvironment (TME) plays a crucial role in shaping immune responses and tumor progression. Immune checkpoint molecules, like B7-H3, are implicated in regulating immune cell functions within the TME. However, the precise mechanisms and interactions remain poorly understood. Furthermore, the impact of oxylipins, particularly 12-HETE, on CD8+ T cell function and survival in the ovarian cancer TME is relatively unexplored.
Methods
To investigate these aspects, we employed anti-MSLN CAR-T cells engineered to target ovarian cancer cells with high MSLN expression. These cells served as a valuable tool for conducting both in vitro and in vivo experiments. Simultaneously, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) screening, we identified the critical role of the oxidized lipid 12-HETE in promoting the survival of CD8+ T cells. Additionally, through structure-based high-throughput virtual screening, we pinpointed the inhibitor, which targets 12-HETE.
Results
We explored the metabolic alterations in CD8+ T cells during cytotoxicity and discovered that nutrient conditions mimicking the TME impaired CD8+ T cell function and survival. Furthermore, we identified the presence of oxylipins, particularly 12-HETE, in the ovarian cancer TME, which negatively affected CD8+ T cell cytotoxicity and survival. Oxylipin 12-HETE secretion was found to be related to tumor cell metabolic rewiring and inhibition of 12-LOX by B7-H3. The inhibitory effect of 12-HETE on T cells was associated with the GPR31 receptor, and it was determined that B7-H3 could bind and activate HRas, consequently suppressing FOXO3 transcriptional activity. Importantly, we identified the small molecule compound HI-TOPK-032 as an inhibitor of B7-H3 expression, which enhanced immune therapy effects.
Conclusions
These findings highlight the potential of targeting B7-H3 and its downstream pathways, including the GPR31-12-HETE axis, as promising avenues for enhancing immune therapy efficacy in ovarian cancer treatment. Furthermore, the identification of the small molecule inhibitor HI-TOPK-032 provides a potential pharmacological strategy to mitigate B7-H3-mediated immune suppression and amplify therapeutic responses.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This study was funded by the Beijing Hospitals Authority’s Ascent Plan (Code: DFL20221201); Gynecological Tumor Precise Diagnosis and Treatment Innovation Studio.
Disclosure
All authors have declared no conflicts of interest.