Targeting Epigenetic Modification of T-Cell Inflamed Signature to Enhance Immune Checkpoint Inhibitors Response in Small Cell Lung Cancer

Abstract

<b>Abstract ID 53622</b> <b>Poster Board 435</b> Small cell lung cancer (SCLC) is a more aggressive type of lung cancer with a worse prognosis. Immune checkpoint inhibitors (ICIs) showed effectiveness against SCLC, however, the response rate was low. Several studies have reported that therapeutic efficacy of ICIs was improved when the tumor microenvironment (TME) exhibited inflamed phenotype including the expression of a T-cell inflamed signature which is a set of genes associated with T-cells and dendritic cells anti-tumor response. The induction of this signature can predict ICI effectiveness. However, epigenetic modifications such as DNA methylation can switch the TME into non-inflamed phenotype and eventually lead to ICI resistance. The aim of the study was to investigate the alterations in DNA methylation levels of T-cell inflamed signature genes in SCLC. Publicly available 450K DNA methylation array data of SCLC was used for our in silico analysis. CpG sites at promoter region of the T-cell inflamed genes were profiled, evaluated, and differentially methylated sites with a methylation difference (delta beta) of ≥ 5% were selected. The investigation was conducted on a dataset containing 13 controls and 11 SCLC cases. The analysis revealed that 18 of the total 37 T-cell inflamed signature genes, including <i>CCL2, CCL5, CD27, CD276, CD4, CMKLR1, FOXP3, GZMB, GZMK, IDO1, IFNG, IRF1, LAG3, NKG7, PRF1, PSMB10, TIGIT, and TNF</i>, had at least one differentially methylated site at the promotor area and 15 of them had at least two sites. The differentially methylated genes were hypermethylated in SCLC with methylation differences ranging between 5 % and 36 %. Interestingly, <i>LAG3</i> and <i>PRF1</i> were the most densely methylated genes with eight differentially methylated sites at the promoter region (average methylation difference = 23% and 17%, respectively). Our discovery of changes in DNA methylation status of T-cell inflamed genes in SCLC can open a novel avenue for targeting this epigenetic modification to reprogram TME and promote ICI susceptibility. Moreover, our data provided support for a novel therapeutic approach of combining hypomethylating agents such as decitabine or azacytidine with ICIs to improve their outcomes in SCLC. However, additional in&nbsp;vitro and in&nbsp;vivo studies are required to validate our results.