Unveiling prostaglandin D2 signaling axis in the tumor microenvironment for immune modulation and prognosis in lung adenocarcinoma.

Abstract

e20057 Background: Tumor metabolism reprogramming is a hallmark of cancer, but metabolite-mediated intercellular communication remains poorly understood. To address this gap, our study employed MEBOCOST, a tool for metabolite abundance estimating and communication events exploring based on single-cell RNA data, to explore the metabolic landscape of tumor microenvironment (TME) in lung adenocarcinoma (LUAD) and identify novel metabolite signaling axis. Methods: The scRNA-seq dataset was subjected to dimensionality reduction using the Seurat package. Cell annotation was manually performed using typical markers from Cell Marker 2.0 and previous studies. Single-cell metabolite abundance and communication events were inferred using MEBOCOST. The TCGA-LUAD datasets was used to estimate and analyze immune cell infiltration levels and tumor hot score using ESTIMATE and ssGSEA algorithms. Additionally, survival analysis was conducted by genes within relative signaling axis. All analysis above in TCGA-LUAD datasets was validated by two Gene Expression Omnibus (GEO) datasets. Results: Five landmark metabolites across cell types were identified as prostaglandin D2 (PGD2), D-Mannose, Choline, L-Cysteine, and Cholesterol of TME in LUAD. Prostaglandin D2 (PGD2) emerged as a key player, primarily produced by fibroblasts and plasmacytoid dendritic cells (pDCs) by via the PTGDS gene and by mast cells via the HPGDS gene. PGD2 signaling was shown to primarily be received by the PGD2 receptor ( PTGDR ) on NK/T cells and transported by the SLCO2A1 transporter on endothelial cells. CX3CR1 + NK/T cells, which are prominent cytotoxic populations, as a PGD2 autocrine signaling axis, are involved in PGD2 autocrine signaling, while KLRC2+ NK, DNAJB1+ NK cells and CD8+ MAIT cells participate in PGD2 paracrine signaling. PGD2 may also assist lactate efflux via SLCO2A1 on endothelial cells. The clinical relevance of the PGD2 signaling axis was validated across multiple bulk RNA datasets, showing that it is associated with the infiltration of above immune cells such as DNAJB1+ NK cells, and linked to better prognosis in LUAD. Furthermore, we found that a risk model developed based on this signaling axis could predict responses to immune therapy in hot and cold tumors, suggesting potential drugs that may benefit low-risk patients. Conclusions: In this study, we identified PGD2 as a critical metabolite within the LUAD tumor microenvironment, facilitating intercellular communication through its signaling axes. The analysis revealed that PGD2 mediates its tumor-suppressive effects by activating immune cells, particularly NK/T cells, which could be important for modulating anti-tumor immune responses. Our findings also highlight its potential as a biomarker for prognosis and a target for future combination therapies.