Chromatin accessibility of circulating CD8+ T cells predicts treatment response to PD-1 blockade in patients with gastric cancer

• Published in: Nature communications 2021-02, Vol.12 (1), p.975-975, Article 975
• Main Authors: Shin, Hyun Mu, Kim, Gwanghun, Kim, Sangjib, Sim, Ji Hyun, Choi, Jiyeob, Kim, Minji, Kwon, Minsuk, Ye, Sang-Kyu, Lee, Dong-Sup, Cho, Seung Woo, Kim, Seung Tae, Lee, Jeeyun, Kim, Hang-Rae
• Format: Article
• Language: English
• Subjects: 45; 45/47; 692/308/575; 692/4028/67/1504/1829; Accessibility; Biomarkers; Biomarkers, Tumor; Blood circulation; Cancer; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; Chromatin; Chromatin Immunoprecipitation Sequencing; Epigenetics; Gastric cancer; Genome; Genomes; Genomics; Humanities and Social Sciences; Humans; Immunotherapy; Lymphocytes; Lymphocytes T; Metastases; Metastasis; Monoclonal antibodies; multidisciplinary; Patients; PD-1 protein; Pembrolizumab; Peripheral blood; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Science; Science (multidisciplinary); Sequence Alignment; Sequence Analysis, DNA; Stomach Neoplasms - genetics; Stomach Neoplasms - therapy; Targeted cancer therapy; Therapy; Transposase; Transposases - genetics; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21299-w

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. Anti-PD-1 therapy could induce a durable response in patients with gastric cancer, however biomarkers to predict response to immunotherapy are generally lacking. Here the authors report that openness of chromatin in circulating CD8 + T cells predicts treatment outcome in patients with metastatic gastric cancer treated with pembrolizumab.