Tumor and Peritoneum-Associated Macrophage Gene Signature as a Novel Molecular Biomarker in Gastric Cancer.

A spectrum of immune states resulting from tumor resident macrophages and T-lymphocytes in the solid tumor microenvironment correlates with patient outcomes. We hypothesized that in gastric cancer (GC), macrophages in a polarized immunosuppressive transcriptional state would be prognostic of poor survival. We derived transcriptomic signatures for M2 (M2 TS , MRC1 ; MS4A4A ; CD36 ; CCL13 ; CCL18 ; CCL23 ; SLC38A6 ; FGL2 ; FN1 ; MAF ) and M1 (M1 TS , CCR7 ; IL2RA ; CXCL11 ; CCL19 ; CXCL10 ; PLA1A ; PTX3 ) macrophages, and cytolytic T-lymphocytes (CTL TS , GZMA ; GZMB ; GZMH ; GZMM ; PRF1 ). Primary GC in a TCGA stomach cancer dataset was evaluated for signature expressions, and a log-rank test determined overall survival (OS) and the disease-free interval (DFI). In 341 TCGA GC entries, high M2 TS expression was associated with histological types and later stages. Low M2 TS expression was associated with significantly better 5-year OS and DFI. We validated M2 TS in prospectively collected peritoneal fluid of a GC patient cohort ( n = 28). Single-cell RNA sequencing was used for signature expression in CD68 + CD163 + cells and the log-rank test compared OS. GC patients with high M2 TS in CD68 + CD163 + cells in their peritoneal fluid had significantly worse OS than those with low expression. Multivariate analyses confirmed M2 TS was significantly and independently associated with survival. As an independent predictor of poor survival, M2 TS may be prognostic in primary tumors and peritoneal fluid of GC patients.