165MO - Single-cell characterization of differentiation trajectories and drug resistance features in gastric cancer with peritoneal metastasis

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 1 clinical trial (n = 20, NCT03710265) and immunotherapy cohort (n = 499) within our center were 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.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

The National Natural Science Foundation of China.

Disclosure

All authors have declared no conflicts of interest.