Hyun Mu Shin^1,2,3,12,*, Gwanghun Kim^2,3,4,12, Sangjib Kim^5,12, Ji Hyun Sim^4,12, Jiyeob Choi^2,6, Minji Kim^2,3,4, Minsuk Kwon⁷, Sang-Kyu Ye^2,3,8,9, Dong-Sup Lee^1,2,3,4,9, Seung Woo Cho¹⁰, Seung Tae Kim⁷, Jeeyun Lee^7,11,* & Hang-Rae Kim^1,2,3,4,9,*

¹Wide River Institute of Immunology, Seoul National University, Hongcheon, Republic of Korea.
²Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
³BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁴Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁵Department of Mathematics, College of Science, Korea University, Seoul, Republic of Korea.
⁶Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁷Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
⁸Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁹Medical Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
¹⁰Department of Biomedical Engineering, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
¹¹Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, Korea.
¹²These authors contributed equally: Hyun Mu Shin, Gwanghun Kim, Sangjib Kim, Ji Hyun Sim.

^*Corresponding author

Although tumor genomic profiling has identified small subsets of gastric cancer (GC) patients with clinical benefit from anti-PD-1 treatment, not all responses can be explained by tumor sequencing alone. We investigate epigenetic elements responsible for the differential response to anti-PD-1 therapy by quantitatively assessing the genome-wide chromatin accessibility of circulating CD8⁺ T cells in patients’ peripheral blood. Using an assay for transposase-accessible chromatin using sequencing (ATAC-seq), we identify unique open regions of chromatin that significantly distinguish anti-PD-1 therapy responders from non-responders. GC patients with high chromatin openness of circulating CD8⁺ T cells are significantly enriched in the responder group. Concordantly, patients with high chromatin openness at specific genomic positions of their circulating CD8⁺ T cells demonstrate significantly better survival than those with closed chromatin. Here we reveal that epigenetic characteristics of baseline CD8⁺ T cells can be used to identify metastatic GC patients who may benefit from anti-PD-1 therapy.