Abstract 2822: RBM10 mutations remodel tumor microenvironment of lung adenocarcinoma and contribute to its progression

Abstract

Abstract Background RBM10 is frequently mutated in lung adenocarcinoma (LUAD). Several studies identified RBM10 could regulate proliferation and apoptosis, but how can RBM10 mutations affect tumor microenvironment (TME) is elusive. We aimed to explore the effect of RBM10 mutations on TME. Methods Whole-exome sequencing (WES) was performed on 39 treatment-naïve early-stage LUADs presenting as ground-glass nodules (GGN). Data from TCGA database (n=562) and WES and RNA-sequencing (RNA-seq) data of another Chinese LUAD cohort (n=128, CHOICE_ADC cohort) were obtained. GSEA was performed to determine immune related pathways. Single-sample GSEA (ssGSEA), CIBERSORT and TIMER were used to evaluate immune infiltration. TIDE was used to calculate the predictive immunotherapy response. Results RBM10 mutational frequency in TCGA and CHOICE_ADC cohort were 7% and 8%, but reached 28% in GGN cohort. Because there were more early-stage LUADs in our cohort, RBM10 more likely mutated in early-stage LUAD. Additionally, majority of RBM10 mutations were protein-truncating variants, including nonsense and frameshift mutation. Survival analysis revealed RBM10 deficiency was related to shorter overall survival. GSEA was performed using RNA-seq data from TCGA and CHIOCE_ADC cohort and revealed immune related pathways were enriched in RBM10 deficient population. In TCGA cohort, the inflammatory response and TGF-β signaling were two of the representative enriched pathways. Similarly, the interferon-γ response and TNF-α signaling via NF-κB were two of the most enriched pathways in CHOICE_ADC cohort. The number of neoantigen and tumor mutation burden were higher in patients with RBM10 mutations. We further compared HLA expression between patients with RBM 10 mutations and wild-type population and found numerous HLAs showed higher expression in RBM10 deficient population, such as HLA.DRB6, HLA.DRB5 and HLA.DQA1. By using ssGSEA, we found diverse immune signatures (Th1 cells, macrophages, DC and CD8+T cells) showed higher enrichment levels in population with low RBM10 expression in both TCGA and CHOICE_ADC cohort. Similarly, RBM10 expression had a positive correlation with the levels of myeloid dendritic cell, macrophage, neutrophil, CD8+T cell and CD4+T cell according to the results of TIMMER and CIBERSORT. Finally, we found PD-L1 and TIM3 exhibited higher expression in population with RBM10 deficiency. Additionally, the predicted immunotherapy response was calculated through TIDE algorithm. Expression of IFNG was upregulated and immune evasion level was lower in population with RBM10 deficiency. Conclusion RBM10 mutations were more common in early-stage LUADs. Immune activity in patients with RBM10 mutations was elevated and there were more neoantigens in these patients. Our results demonstrated that LUAD patients with RBM10 mutations could more likely benefit from immunotherapy. Citation Format: Bing Liu, Yang Chen, Nan Wu. RBM10 mutations remodel tumor microenvironment of lung adenocarcinoma and contribute to its progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2822.