Epigenomic preconditioning of peripheral monocytes determines their transcriptional response to the tumor microenvironment

Monocytes are recruited to tumors and undergo transcriptional reprogramming resulting in tumor-promoting functions. Epigenomic features, such as post-translational modification of histones and chromatin accessibility, are key determinants of transcription factor binding and thereby play an important role in determining transcriptional responses to the tissue environment. It remains unknown whether systemic tumor-associated signals could alter the epigenomic landscape of peripheral monocytes before they reach the tumor, thus shaping their subsequent response to the tumor microenvironment. Here, we performed genome-wide analyses of multiple histone modifications (H3K4me1, H3K4me3, H3K27ac) and chromatin accessibility in a mouse model and found that the distal tumor caused extensive remodeling of both H3K4me3+ promoters and H3K4me1+ enhancers in peripheral monocytes. Specifically, this involved the repression of interferon-responsive regulatory elements as well as the stablishment of enhancers harboring binding motifs for transcription factor families downstream of pro-inflammatory signaling, such as C/EBP, AP-1 and STAT. Reprogrammed enhancers in peripheral monocytes could be linked to sustained gene expression changes that persisted after tumor infiltration. In addition, key pro-tumor genes upregulated in tumor-infiltrating monocytes showed epigenetic priming already in the circulation. Overall, these results indicate that the epigenomic landscape of peripheral monocytes is altered in response to a distal tumor, and this can shape the transcriptional response of monocytes to the tumor microenvironment. Overall design: Transcriptomic and epigenetic profiling of Ly6C-hi monocytes from tumor-bearing and healthy mice using high-throughput sequencing (RNA-seq, ATAC-seq, H3K4me3 CUT&Run, H3K4me1 CUT&Tag, H3K27ac CUT&Tag).