Abstract 1179: A single-cell atlas of human gastric malignancy reveals CD8+ T cell rejuvenation as a mediator of immunotherapeutic response

Abstract Immune checkpoint inhibition (ICI) has emerged as a mainstream treatment for patients with advanced stage gastric cancer (GC). Cellular heterogeneity in the tumor microenvironment (TME) has a profound impact on the therapeutic responses to ICI. Here we characterize the kinetics of tumor-infiltrating immune populations in GC patients treated with anti-PD-1 using single-cell RNA and TCR sequencing (scRNA/TCR-seq), including primary tumors and metastases. Integrated with public GC scRNA-seq datasets, we construct the largest multi-omic atlas of GC cell states to date that captures the full trajectory of GC malignancy and comprises >320,000 cells derived from 73 samples. We demonstrate the rejuvenation of exhausted CD8+ T cells into a proliferative state marked by the loss of LAYN expression as a major mediator of ICI response in the TME. In parallel, we observe enhanced immunogenicity of cancer cells in post-ICI tumors, thus highlighting the coordination between tumor-intrinsic and microenvironmental factors elicited by ICI. Our study provides a valuable resource of investigating the tumor response to anti-PD-1 treatment and suggests novel strategies for combination therapy and patient stratification. Citation Format: Han Liang, Jian Chen, Yikai Luo, Muxing Kang, Wei Liu, Lie Wang. A single-cell atlas of human gastric malignancy reveals CD8+ T cell rejuvenation as a mediator of immunotherapeutic response [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 1179.