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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 (6Suppl): Abstract nr 1179.
Liang et al. (Fri,) studied this question.