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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 (Tumor₁, Tumor₂, and Tumor₃) were identified. Trajectory analysis revealed the differentiation of chief cells into Tumor₁, subsequently dividing into more malignant cell types, Tumor₂ and Tumor₃. Tumor₂ was enriched in IM, while Tumor₁ was enriched in HM and HIM. Patients grouped by Tumor₁, 2, 3 levels showed varying survival outcomes. Surprisingly, high Tumor₂ levels correlated with increased survival, attributed to elevated HLA and PDL1 expression, promoting immune cell recruitment and robust response to IO therapy. Conversely, Tumor₃ 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 Tumor₁ and Tumor₂. Through TCR analysis, we found heightened clonality in both CD8 effector cells and exhausted T cells in patients with elevated Tumor₁ and Tumor₂ 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 Tumor₂ patients emphasizes the potential of targeting specific pathways for improved therapeutic outcomes. Additionally, the observed T cell dynamics and clonality in Tumor₁ 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 (6Suppl): Abstract nr 5667.
Gu et al. (2024) studied this question.