141P - Immune-related epigenomic and transcriptomic signatures to predict immunotherapy response in NSCLC

Background

Immunotherapy based on Immune Checkpoint Inhibitors (ICI) has changed the management of advanced Non-Small Cell Lung Cancer (NSCLC), achieving long-time responders for the first time. However, response rates remain below 40%. A deeper understanding of ICI response mechanisms and the identification of predictive biomarkers is still an urgent need. A close relation between DNA methylation and the immunogenic status of the tumor microenvironment (TME) has been recently proposed for several solid tumors. In this work we evaluated the epigenetic and transcriptomic status of NSCLC tumors before immunotherapy to disclose the possible role of DNA methylation in ICI response, and to identify immune-related signatures that predict ICI outcome.

Methods

We included 24 advanced NSCLC patients treated with anti-PD1 at first line. DNA and RNA were extracted from FFPE tumor biopsies. Genome-wide DNA methylation was quantified with the MethylationEPIC array and RNA-seq was performed with a NovaSeq6000 system. Data was annotated to the GRCh38 genome and bioinformatics was performed with R/Bioconductor.

Results

Differential methylation and expression patterns were found between patients with radiological response (n=10) and non-responder patients (n=14). We identified a DNA methylation signature that predicts a 6-months response to anti-PD1 therapy. Also, we reported a methylation profile associated with longer progression-free survival (PFS). Functional consequences of differential DNA methylation were confirmed by RNA-seq, identifying dysregulated immune pathways significantly enriched for both methylation and transcriptomic signatures. Pathways associated to ICI response related to T-cell and toll-like receptors signaling pathways, MHC-II complex, and interleukins. We also found aberrant methylation of the PI3K-Akt signaling pathway, which plays an essential role in the TME, regulating immune checkpoints and the sensitivity to ICI.

Conclusions

Overall, our results confirm that DNA methylation plays a role in the response to ICI in advanced NSCLC. These immune-related methylation profiles can predict response to anti-PD1 therapy and correlate with longer PFS, representing a source of predictive biomarkers for ICI outcome.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

This research project is funded by the national Institute of Health Carlos III (ISCIII, PI21/00348). M.M-F. is supported by the Miguel Servet program (CP20/00188) from the ISCIII and the European Social Fund (“Investing in your future”).

Disclosure

All authors have declared no conflicts of interest.