Abstract 2008: Intra-tumoral NK cell number is associated with immune response, and combination of it and clinical features is a strong prognostic biomarker in gastric cancer

Abstract Background: The number of Natural Killer (NK) cell infiltration has been implicated for prognosis of gastric cancer patients. However, tumor immune microenvironment of gastric cancer patients with high NK cell infiltration has not yet been fully investigated. Methods: NK cell infiltration fraction of gastric cancer in total 831 patients was quantified by using xCell algorithm, and its clinical relevance was investigated in gastric cancer patients at our institution (Yokohama City University Hospital (YCU), and publicly available cohorts with transcriptome (TCGA, GSE84437 and GSE167036), and single cell sequence cohort (GSE150290). Results: In the single cell sequencing cohort, the distribution of NK cells was similar to that of NK cell-related gene expression, including PRF1, NKG7, NCR1, GZMB, KLR-B1/C1/D1, and IFNG. High NK cell infiltration in gastric cancer correlated with enriched immune gene sets, such as interferon (IFN)-α and IFN-γ responses (all normalized enrichment score (NES) > 1.50, and all false discovery rate (FDR) < 0.20), and also linked to increased cytolytic activity and low stromal cell infiltration, including fibroblasts, lymphatic/microvascular endothelial cells, pericytes, and adipocytes (all p < 0.05), consistently in both TCGA and GSE84437 cohort. Gastric cancer with high NK cell infiltration was also significantly associated with higher mutation rates (p < 0.01). However, they did not enrich with several pro-cancerous hallmark cancer gene sets, such as angiogenesis, epithelial mesenchymal transition, hypoxia, nor apoptosis. Clinically, high NK cell infiltration was associated with better overall survival (p = 0.023 in GSE84437, and p = 0.015 in TCGA). Interestingly, as the treatment response of chemotherapy improved, the infiltrating fraction of NK cell increased (p = 0.012 in YCU cohort). Furthermore, the NK cell score was independent factor for patient survival. Additionally, combining NK cell score with clinicopathological factors, including age at a diagnosis, AJCC T- and N-category, provided a powerful prognostic score for gastric cancer patients, consistently in multiple cohorts (p < 0.001, hazard ratio (HR) = 1.96 in TCGA, and p = 0.017, HR = 2.73 in the YCU cohort). Conclusions: Gastric cancer with high NK cell infiltration is associated with increased immune activity and lower stromal cell infiltration. Combining clinicopathological factors with NK cell score may provide a powerful tool as prognostic predictor for gastric cancer patients. Citation Format: Masanori Oshi, Yuko Tamua, Rongrong Wu, Li Yan, Colin J. Rog, Kizuki Yuza, Takashi Ishikawa, Itaru Endo, Kazuaki Takabe. Intra-tumoral NK cell number is associated with immune response, and combination of it and clinical features is a strong prognostic biomarker in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2008.