Abstract
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.
Highlights
Tumor genomic profiling has identified small subsets of gastric cancer (GC) patients with clinical benefit from anti-programmed death-1 (PD-1) treatment, not all responses can be explained by tumor sequencing alone
For discovery cohort, cryopreserved blood lymphocyte samples from metastatic gastric cancer (mGC) patients participating in a phase II pembrolizumab monotherapy clinical trial[5] were used in this study
Clinical characteristics of all patients with mGC are provided in Supplementary Tables 1 and 2
Summary
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. Chronic stress[9,10,11] caused by factors such as pathogens, microbiota, acidity, hypoxia, glucose deprivation, and the tumor microenvironment can cause epigenetic changes[12,13] that lead to subtle to profound alterations in the immune system[14,15] These host-tumor interactions can alter epigenetic characteristics of circulating CD8+ T cells which may increase or decrease response to anti-PD-1 treatment in cancer patients[16,17]. MGC patients with high openness chromatin of CD8+ T cells show longer PFS following anti-PD-1 treatment when compared to those with closed chromatin These results present that openness of chromatin at specific genomic positions of baseline circulating CD8+ T cells can predict clinical outcome to treatment response following anti-PD-1 treatment
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
