29P Non-diploidy related prognostic molecular signature (NPMS) predict an “immunologically hot” phenotype in squamous cell lung cancer

Abstract

Lung squamous cell carcinoma (LUSC) patients suffer from less targetable onco-drivers and potentially acquire clinical benefit from immune checkpoint inhibitors (ICIs). DNA content aberrations contribute to genomic instability and are initial events of tumorigenesis. We established a non-diploidy related prognostic molecular signature (NPMS) based on differentially expressed genes (DEGs) and investigated the immune features of it. We conducted a retrospective analysis based on data downloaded from TCGA database. By integrating CNA and SNV via ABSOLUTE algorithm, we obtained the DNA ploidy status and divided patients into near-diploid and non-diploid group. DEGs were selected and gene functional enrichments were carried out. NPMS was established by all subset multivariate Cox regression to further stratify patients and validated by integrative analysis of GSE73403, GSE41271, GSE4212. Gene sets enrichment analysis was applied to further figure out the mechanism behind NPMS. Non-diploidy coincided with higher TMB and intratumor heterogeneity. Functional enrichment indicated that DEGs mainly participated in genomic instability. NPMS containing HOXB5, TINAGL1, POLR3GL, APOB, FABP6, SCARF1 was established. Patients with low score had better OS than those with high score (HR 0.60, 95%CI 0.45-0.79, p-value=0.000321). This was validated in the GEO cohorts (HR 0.57, 95%CI 0.37-0.88, p-value=0.0121). Dysregulation of DNA repair and cell cycle checkpoints were higher enriched in high score group. The immune phenotype of high score tended to be "immunologically hot", which was characterized as high density but low activity immune cells infiltrated, accompanied by expression of higher immunosuppressive factors, such as PD-1, CTLA4, IDO1. Meanwhile, the upregulation of IFN-γ signaling pathway, lipid alternation and the high correlation between them were observed. High NPMS score corresponded with an "immunologically hot" feature thereby led to shorter OS. The crosstalk of upregulated IFN-γ signaling and aberrations of tumor metabolism mignt participate. It's rational to deduced that patients with high score might be the potential ICIs benefited subpopulation.