Genome-wide methylation patterns predict clinical benefit of immunotherapy in lung cancer

Abstract

Background: It is crucial to unravel molecular determinants of responses to immune checkpoint blockade (ICB) therapy because only a small subset of advanced non-small cell lung cancer (NSCLC) patients responds to ICB therapy. Previous studies were concentrated on genomic and transcriptomic markers (e.g., mutation burden and immune gene expression). However, these markers are not sufficient to accurately predict a response to ICB therapy. Results: Here, we analyzed DNA methylomes of 141 advanced NSCLC samples subjected to ICB therapy (i.e., antiprogrammed death-1) from two independent cohorts (60 and 81 patients from our and IDIBELL cohorts). Integrative analysis of patients with matched transcriptome data in our cohort (n = 28) at pathway level revealed significant overlaps between promoter hypermethylation and transcriptional repression in nonresponders relative to responders. Fifteen immune-related pathways, including interferon signaling, were identified to be enriched for both hypermethylation and repression. We built a reliable prognostic risk model based on eight genes using LASSO model and successfully validated the model in independent cohorts. Furthermore, we found 30 survival-associated molecular interaction networks, in which two or three hypermethylated genes showed significant mutual exclusion across nonresponders. Conclusions: Our study demonstrates that methylation patterns can provide insight into molecular determinants underlying the clinical benefit of ICB therapy.

Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation

“…One such mechanism that has been observed in several cancer types is hypermethylation of the promoters or enhancers of these genes. This modification has been documented in the regulatory elements of MHC I ( 176 , 181 – 183 ), TAP ( 128 ), Tapasin ( 184 ), IFNR pathway components ( 185 – 187 ). This DNA modification silences gene expression by recruiting repressive factors, such as methyl-CpG binding domain protein 1 (MBD1) and methyl-CpG binding protein 2 (MeCP2) and interfering with transcription.…”

DNA methylation as predictive marker of response to immunotherapy?

“…Unfortunately, the authors did not provide information about the predictive value of FOXP1 methylation in their patient cohort. Noteworthy, the clinical benefit in this cohort was not associated with TMB, neo-antigen load, aneuploidy level or PD-L1 expression [31].…”

“…A similar approach to identify a set of CpG sites predictive for response to anti-PD-1/PD-L1 therapy in advanced NSCLC patients was published by Kim et al [31]. In this study, tumor samples of 60 NSCLC patients were analyzed using MethylationEPIC bead-Chips and 377 differentially methylated CpG sites between responders and nonresponders were identified.…”

“…In this study, tumor samples of 60 NSCLC patients were analyzed using MethylationEPIC bead-Chips and 377 differentially methylated CpG sites between responders and nonresponders were identified. The vast majority of these CpG sites were hypomethylated in nonresponders [31]. Based on these data, the authors calculated a predictive methylation model consisting of 8 genes (IRF6, CTSD, GRN, LTBR, TRIM36, EVL, CD3E and LCP1).…”

Prognostic and Predictive Biomarkers in Non-Small Cell Lung Cancer Patients on Immunotherapy—The Role of Liquid Biopsy in Unraveling the Puzzle

“…More recently, immune checkpoint inhibitor agents targeting programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) have been established as a new treatment for advanced NSCLC patients. Of note is that a minority of NSCLC patients (< 20%) respond to this expensive therapy when administrated in monotherapy [ 6 , 7 , 8 , 9 ]. Immunotherapy is often given in combination with chemotherapy since several chemotherapeutical compounds appear to have the capacity to upregulate PD-L1 expression on cancer cells and to promote antitumor immunogenicity [ 10 ].…”