NC. Pan-cancer methylation combined immune escape.

What Xiaobian pushed for you today is an article published in the magazine Nature communications (if: 11.8) in September this year.DNA methylation loss promoters immune evaluation of tumours with high mutation and copy number loaddna methylation deletion promotes immune escape cell mitosis of tumors with high mutation and copy number load, and increases tumor mutation load and copy number load is a predictive marker for clinical benefit of immunotherapy.it has been found that the immunoregulatory pathway genes are concentrated in the late replicative partial methylation domain and are transcriptionally suppressed in demethylated tumors with hypermethylation of CpG island promoter.loss of global methylation was associated with immune escape characteristics, but not with mutation load and aneuploidy.the TCGA data of various tumor types were systematically analyzed, and the relationship between global methylation level and cell proliferation, mutation load, scna level, invasive immune cell markers and immune response gene activity was studied.hypotheses derived from molecular analysis were tested using a lung cancer cohort, the first study to address DNA methylation patterns in molecular and clinical data for cancer immunotherapy.the results show that as an important predictive marker in immunotherapy, genomic demethylation is related to epigenetic regulation, and can be used as a combined regimen of precise immunotherapy.results global methylation was correlated with immune characteristics. Pan cancer analysis of TCGA data showed that markers of cell proliferation were closely related to mutation load and aneuploidy between cancer types.genomic demethylation methods based on nuclide-1 probes are also closely related to cell proliferation markers (Fig. 1a).deletions of methylation were also associated with increased mutation load (Fig. 1b) and chromosome scna load (Fig. 1c).the study found a correlation between global L1 methylation levels and immune markers (Fig. 1D).based on the sample level characteristics, multiple regression analysis was performed on the expression level of each gene. It can be determined that the immune invasion is related to global methylation level, but not to mutation load and aneuploidy when adjusting purity, age and tumor stage (Fig. 2A).a significant correlation with genomic demethylation was also observed, which should include the immunomodulatory pathway of genes expressed in tumor cells (Fig. 2b).the correlation between cell proliferation markers and immunomodulatory genes was opposite (Fig. 2b).Figure 1 Correlation of global DNA methylation levels Figure 2 deletion of genomic methylation associated with immune escape characteristics suppression of immune genes in late replication regions identified genes that replicate earlier or later in cancer than normal cells through cell line data.it was found that genes that replicate in late stage of cancer were significantly inhibited in demethylated tumors with CpG island (CGI) promoter hypermethylation (Fig. 3a, b), and early replicating genes tended to be overexpressed in demethylated tumors (Fig. 3C).immune related pathways were overexpressed in the late replication region, while cell cycle genes were concentrated in the early replication region (Fig. 3D).replication gene enrichment pathways in advanced cancer include cytokine receptor interaction, interferon - α / β (IFN - α / β) signaling and Rig-1 / MDA5 mediated IFN - α / β induction (Fig. 3e).contrary to the data obtained from intratumoral demethylation, treatment with methylation inhibitors has shown to induce endogenous retrovirus (ERV) and double stranded RNA derived from lines, leading to the activation of IFN - α / β response in cancer.the expression levels of ERV and L1 in tumor samples were measured, and the correlation between their expression levels and cytotoxic immune activity indexes was usually negative, which indicated that IFN - α / β silencing covered the immune stimulation effect of ERV / L1 expression through genome demethylation.Figure 3 gene characteristics of the late replication region. Inhibition of immune genes in the partial methylation domain. The loss of methylation in the late replication region is related to the formation of a heterochromatic structure called partial methylation domain (PMD). Some studies have shown that PMD demethylation is a common feature of many cancer types.genes in PMDS of various types of cancer are largely silenced due to the formation of inhibitory chromatin structure or the hypermethylation of CGI.the methylation variability and replication timing of PMD lead to three distinct subclasses (FIG. 4A).the characteristics of PMD are related to the genome length, while the shorter PMD replication time is earlier (FIG. 4A, b).immunomodulatory pathway genes involved in antigen processing and presentation, cytokine receptor interaction, and JAK-STAT signaling pathway were concentrated in short PMD (Fig. 4C, d).inf - α family genes were found in short PMD (Fig. 4e).there are 8 HLA genes in the short PMD, which is consistent with the late replication region (Fig. 3a, b). Short PMD is associated with gene suppression (Fig. 4F) and CGI hypermethylation (Fig. 4G) in demethylated tumors.the enriched immune genes (Fig. 4C, d) were significantly concentrated near the PMD boundary (Fig. 4h), indicating that these genes are particularly prone to promoter methylation.the global methylation prediction response to immunotherapy is predicted by the gene characterization in the methylation domain in part 4 of the lung cancer anti PD-1 / PD-L1 cohort. Methylation group and exon group data were generated from 60 samples from the lung cancer anti PD-1 / PD-L1 cohort, and the anti PD-1 lung cancer cohort consisted of 81 methylation groups and 22 exon groups.for validation, data from 40 TCGA melanoma patients receiving immunotherapy were used, and figure 5A provides information on these three cohorts.according to the level of L1 methylation, the lung cancer cohort samples were divided into hypomethylation group and hypermethylation group.the hypomethylation population showed decreased genomic methylation and increased CGI methylation (Fig. 5b, c).consistent with Pan cancer molecular data analysis, global hypomethylation samples showed high mutation load and aneuploidy and CGI hypermethylation in short PMD (Fig. 5d). transcriptome data from SMC and TCGA cohort indicated that genes involved in MHC and cytokine receptor interactions were significantly enriched in SMC and TCGA cohort, which could be used to inhibit global demethylated tumors in both cohort. when the patient sample was stratified according to L1 methylation level, the prognosis of hypomethylation group was poor (Fig. 5e-g). for the combined lung cancer cohort, a total of 82 samples of methylation group and matched exon group data were obtained (Fig. 5a). compared with the global level of L1 methylation, mutation load did not show significant results (Fig. 5H). multivariate regression with survival as the response variable showed that global L1 methylation level had a significant impact, but there was no mutation load at P = 0.05 (Fig. 5H). repeated the univariate comparison of the two lung cancer cohort, SMC cohort and idibell cohort both caused significant stratification through global methylation, but not significantly stratified by mutation load (Fig. 5g, I), and global L1 methylation level was negatively correlated with aneuploidy (Fig. 5d). Pan cancer analysis showed that aneuploidy was related to the characteristics of immune escape. in conclusion, hypomethylation and high aneuploidy are expected to reduce tumor immunity and undermine the clinical benefits of immunotherapy. when examining the SMC lung cancer cohort with available aneuploidy data (Fig. 5a), only global methylation showed a significant correlation between adverse clinical reactions (Fig. 5g). TCGA melanoma cohort repeated this trial and divided the samples into hypomethylation group and hypermethylation group according to L1 methylation level. The hypomethylation group in melanoma summarized the methylation of CGI promoter in short PMD, and had poor response to immunotherapy. neither mutation load nor aneuploidy level can explain the clinical benefit. Fig. 5 genomic demethylation has adverse effects on clinical benefits of checkpoint blocking. Global demethylation excludes the influence of aneuploidy. Global demethylation is significantly correlated with scna of different tumor types (Fig. 6a). The size of chromosome scnas (cscnas) is determined by combining the levels of chromosome scna and arm scna, and the results are compared with focus scnas (fscnas) The correlation was stronger than that of fscna (Fig. 6b). partial correlation was used to estimate the correlation between L1 methylation level and cscna (or fscna) when controlling for fscna (or cscna). in most cases, global hypomethylation is associated with cscna, but not with fscna (Fig. 6c). when cscna is controlled, the correlation with fscna disappears (Fig. 6c). multiple regression analysis of immune characteristic score showed that the global L1 methylation level was significantly higher than the level of cscna (Fig. 6D). partial correlation analysis was performed on immune characteristic score, global L1 methylation level and cscna level. after the level of cscna was controlled, there was a positive correlation between immune characteristic score and global L1 methylation level (Fig. 6e). these results suggest that the immune escape characteristics of highly aneuploid tumors are related to genome demethylation. the aneuploidy in Fig. 6 shows global DNA hypomethylation. 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