Abstract 160P
Background
The function of the peritoneal niche in gastric cancer (GC) peritoneal metastases (PM) remains unclear. We hypothesize that the peritoneum evolves to facilitate homing of tumor seeds and progression.
Methods
Peritoneal samples from GC patients were retrieved during intra-peritoneal therapeutics (n=57, with n=59 paired PM samples) or surgical resection of primary tumor (PT) (n=20) in non-metastatic GC. As controls, benign normal peritoneal samples were retrieved from 11 patients undergoing intra-abdominal operations for non-malignant indications, with 5 samples originating from patients with active peritonitis (benign-inflamed) and 6 samples being retrieved in elective settings (benign-quiescent). Bulk RNA-seq was conducted and samples were clustered to computationally group samples by transcriptome. Deconvoluted immune cell subtypes were compared.
Results
Two clusters emerged: one containing all 6 benign-quiescent samples, resembling an “early” peritoneal metastatic niche (PMN-early). The other cluster, comprising 76.7% of adjacent normal peritoneum in GCPM and all 5 benign-inflamed samples, suggested a reconditioned, inflamed, and immune-infiltrated peritoneum (PMN-late). PMN-late peritoneum correlated with poorer survival (p=0.048). Unexpectedly, 7 samples from early GC patients without PM clustered as PMN-late. Compared to benign-quiescent peritoneum, samples from patients with GCPM and early GC without PM had more activated myeloid dendritic cells, M1 macrophages, cancer associated fibroblasts (CAFs) and T-cells regardless of PMN cluster. PMN-late peritoneum also demonstrates pro-tumorigenic properties with oncogenic pathways such as EMT, hypoxia and TGF-beta signalling pathways being enriched in GCPM samples neighbouring PMN-late (n=34) when compared to PMN-early (n=25) peritoneum. Increased CAFs and plasma B cells in peritoneal samples predicted peritoneal recurrence.
Conclusions
We discover a pro-tumorigenic peritoneal niche phenotype associated with GCPM progression and poor survival. These findings underscore the role of the peritoneum in PM and provide biological insight into mechanisms underpinning niche reconditioning in GCPM.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Medical Research Council, National University Health System, Yong Loo Lin School of Medicine, National University of Singapore.
Disclosure
J.J. Zhao: Financial Interests, Institutional, Funding: National University Hospital, Yong Loo Lin School of Medicine, National University of Singapore. P. Tan: Financial Interests, Personal, Funding: Tempus Healthcare . R. Sundar: Financial Interests, Personal, Other: Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, Eli Lilly, Roche, AstraZeneca, DKSH, MSD, Paxman Coolers, Natera, Astellas, GSK, Ipsen. All other authors have declared no conflicts of interest.