Abstract 5667: Intratumoral heterogeneity in gastric cancer related with survival and tumor microenvironment

Abstract Gastric cancer (GC), often diagnosed at an advanced stage, poses a significant therapeutic challenge due to its resistance to treatment. The understanding of intratumoral heterogeneity, crucial for tumor cell survival, remains limited in GC. We conducted a comprehensive analysis of three patient groups (intraperitoneal metastasis [IM], hematogenous metastasis [HM], and both metastasis [HIM]) undergoing immunotherapy (IO) and chemotherapy. Utilizing single-cell RNA sequencing and TCR sequencing, we examined 11 adjacent normal, 10 HM, 8 IM, and 5 HIM primary GC samples. In epithelial cells, three distinct tumor clusters (Tumor_1, Tumor_2, and Tumor_3) were identified. Trajectory analysis revealed the differentiation of chief cells into Tumor_1, subsequently dividing into more malignant cell types, Tumor_2 and Tumor_3. Tumor_2 was enriched in IM, while Tumor_1 was enriched in HM and HIM. Patients grouped by Tumor_1, 2, 3 levels showed varying survival outcomes. Surprisingly, high Tumor_2 levels correlated with increased survival, attributed to elevated HLA and PDL1 expression, promoting immune cell recruitment and robust response to IO therapy. Conversely, Tumor_3 high patients exhibited worse survival, with enrichment in metabolic pathways associated with glycolysis and hypoxia, linking to metastasis. We observed the proportion of T cells that increased presence of CD8 effector cells among patients exhibiting high levels of Tumor_1 and Tumor_2. Through TCR analysis, we found heightened clonality in both CD8 effector cells and exhausted T cells in patients with elevated Tumor_1 and Tumor_2 levels. This suggests that the activated CD8 effector T cells in these patients may enhance their ability to effectively target and attack cancer cells. In summary, this study provides a comprehensive picture of intratumoral heterogeneity in GC can impact the survival and tumor microenvironment. The unexpected high survival in Tumor_2 patients emphasizes the potential of targeting specific pathways for improved therapeutic outcomes. Additionally, the observed T cell dynamics and clonality in Tumor_1 and 2 underscore the importance of understanding the immune microenvironment for effective cancer attack. Citation Format: Do-eon Gu, Woo Sun Kwon, Sun Young Rha, Woong-Yang Park. Intratumoral heterogeneity in gastric cancer related with survival and tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5667.