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

oleh: Kevin M. Sullivan, Haiqing Li, Annie Yang, Zhifang Zhang, Ruben R. Munoz, Kelly M. Mahuron, Yate-Ching Yuan, Isaac Benjamin Paz, Daniel Von Hoff, Haiyong Han, Yuman Fong, Yanghee Woo

Format: Article
Diterbitkan: MDPI AG 2024-04-01

Deskripsi

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<sub>TS</sub>, <i>MRC1</i>; <i>MS4A4A</i>; <i>CD36</i>; <i>CCL13</i>; <i>CCL18</i>; <i>CCL23</i>; <i>SLC38A6</i>; <i>FGL2</i>; <i>FN1</i>; <i>MAF</i>) and M1 (M1<sub>TS</sub>, <i>CCR7</i>; <i>IL2RA</i>; <i>CXCL11</i>; <i>CCL19</i>; <i>CXCL10</i>; <i>PLA1A</i>; <i>PTX3</i>) macrophages, and cytolytic T-lymphocytes (CTL<sub>TS</sub>, <i>GZMA</i>; <i>GZMB</i>; <i>GZMH</i>; <i>GZMM</i>; <i>PRF1</i>). 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<sub>TS</sub> expression was associated with histological types and later stages. Low M2<sub>TS</sub> expression was associated with significantly better 5-year OS and DFI. We validated M2<sub>TS</sub> in prospectively collected peritoneal fluid of a GC patient cohort (<i>n</i> = 28). Single-cell RNA sequencing was used for signature expression in <i>CD68</i><sup>+</sup><i>CD163</i><sup>+</sup> cells and the log-rank test compared OS. GC patients with high M2<sub>TS</sub> in <i>CD68</i><sup>+</sup><i>CD163</i><sup>+</sup> cells in their peritoneal fluid had significantly worse OS than those with low expression. Multivariate analyses confirmed M2<sub>TS</sub> was significantly and independently associated with survival. As an independent predictor of poor survival, M2<sub>TS</sub> may be prognostic in primary tumors and peritoneal fluid of GC patients.