Abstract 157P
Background
Gastric cancer patients with peritoneal metastasis (GCPM) experience a rapidly deteriorating clinical trajectory characterized by therapeutic resistance and dismal survival, particularly following the development of malignant ascites. However, the intricate dynamics within the peritoneal microenvironment (PME) during treatment process remains largely unknown.
Methods
Matched samples from primary tumors (PT), malignant ascites, and peritoneal metastases (PM), along with paired pre-treatment and post-chemo/immunotherapy progression ascites samples, were collected from 17 patients. These samples were subjected to single-cell RNA sequencing (n = 28) and spatial transcriptomics (n = 3), generating a single-cell landscape comprising 233,986 cells. Furthermore, post-hoc analyses of a phase I clinical trial (n = 20, NCT03710265) and immunotherapy cohort (n = 499) within our center was conducted to validate the findings.
Results
Tracing the evolutionary trajectory of epithelial cells unveiled the terminally differentially MUC1+ cancer cells with a high epithelial-to-mesenchymal transition potential, which correlates with poor prognosis. A significant expansion of macrophage infiltrates, which exhibited highest pro-angiogenic activity, was observed in the ascites compared to PT and PM. Besides, higher C1Q+ macrophage infiltrates correlated with significantly lower GZMA+ T-lymphocyte infiltrates in therapeutic failure cases, potentially mediated by the LGALS9-CD45 and SPP1-CD44 ligand-receptor interactions. In the chemoresistant group, intimate interactions between C1Q+ macrophages and fibroblasts through the complement activation pathway were found. In the group demonstrating immunoresistance, heightened TGF-β production activity was detected in MUC1+ cancer cells. Ultimately, post-hoc analyses indicated that co-targeting TGF-β and PDL1 pathways may confer superior clinical benefits than sole anti-PD-1/PD-L1 therapy for GCPM patients.
Conclusions
Our findings elucidated the cellular differentiation trajectories and crucial drug resistance features within PME, facilitating the exploration of effective targets for GCPM treatment.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Peking University Cancer Hospital and Institute.
Funding
This work was supported by the National Natural Science Foundation of China (82203881, U22A20327), the Beijing Natural Science Foundation (7222021), the Beijing Science and Technology Plan (Z231100007423009), the Beijing Hospitals Authority Youth Programme (QML20231115).
Disclosure
All authors have declared no conflicts of interest.