Abstract 5717: LncRNA RP11-291B21.2 is associated with Durvalumab response in NSCLC and BLCA cancers
Authors: Wu Song , Hsu Sarah , Zhang Qu , Greenlees Lydia , Xiao Mike , Gupta Ashok 
Published: September 2020

Introduction

Long noncoding RNAs (lncRNAs) are interacting with oncogenes, tumor suppressors and immune genes by regulating their expression and activity of relevant transcription factors, RNA-binding proteins, and microRNAs. Dysregulated lncRNAs in immune cells are associated with excessive or uncontrolled inflammation, and play vital roles in innate immune responses, carcinogenesis and tumor microenvironment (TME). Understanding potential associations of lncRNAs with bladder cancer (BLCA) and non-small cell lung cancer (NSCLC) patients treated by ICB agents, such as durvalumab, is emerging.

Methods

RNAseq data from CP1108 (NCT01693562) clinical trial samples (97 NSCLC samples and 66 BLCA samples treated by durvalumab monotherapy) were processed using a comprehensive annotated genome (GRCh38.p12, release 28). The normalized lncRNA expression was reported, significantly differentially expressed lncRNAs between RECIST responders and non-responders in both BLCA and NSCLC patients were then identified using R limma package. Single-cell RNAseq data analysis was done with R Seurat package. Correlation analysis between interested lncRNAs and known oncogenic or immune genes was carried out using Spearman's rho metric in both CP1108 and TCGA RNAseq datasets. Kaplan-Meier survival analysis (OS and PFS) was performed and log-rank p-value was reported.

Results

Eight lncRNAs (RP4-740C4.7, AL1333245.1, RP11-284F21.10, RP5-1139B12.4, RP11-291B21.2, CTD-3064M3.7, TRG-AS1, and RP11-291B21.2) were identified to be differentially expressed between durvalumab responders and non-responders in both CP1108 BLCA and NSCLC tumors. RP11-291B21.2 is the most interested lncRNAs since 6 of 7 its upstream proximity genes (up to 300kb) are killer cell lectin like receptors (KLRs): KLRC1, KLRC2, KLRC3, KLRC4, KLRK1, GABARAPL1, and KLRD1 and they are all significantly correlated with the expression of RP11-291B21.2. Co-expression analysis has shown that lncRNA RP11-291B21.2 is highly correlated with multiple key immune genes, including NK / T cells markers and IFNg induced genes, suggesting its important role in regulating tumor microenvironment. The analysis of scRNAseq data of NSCLC tumors suggests RP11-291B21.2 is dominantly expressed in CD8+ T cells, especially in exhaustive T cells. RP11-291B21.2 is also confirmed to be highly expressed (FC&gt;1.8, p&lt;0.03) in exhausted CD8+ T cells both 40h and day 6 after stimulation in the in vitro experiments. Survival analysis has revealed high expression of RP11-291B21.2 is associated with better survival for patients treated by durvalumab in NSCLC and BLCA (HR=~0.3), but not for patients treated with chemotherapy in TCGA datasets. In conclusion, high expression of RP11-291B21.2 predicts better survival to NSCLC and BLCA patients treated by durvalumab which may suggest that RP11-291B21.2 is a potential lncRNA biomarker to PD1/PDL1 blockage.

Citation Format: Song Wu, Sarah Hsu, Qu Zhang, Lydia Greenlees, Mike Xiao, Ashok Gupta. LncRNA RP11-291B21.2 is associated with Durvalumab response in NSCLC and BLCA cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5717.