RBM10 Deficiency Is Associated With Increased Immune Activity in Lung Adenocarcinoma

Abstract

IntroductionRBM10 is one of the frequently mutated genes in lung adenocarcinoma (LUAD). Previous studies have confirmed that RBM10 could suppress the disease progression and cell proliferation in LUAD, but its loss-of-function mutations are more frequent in early-stage disease and decrease with the advancement of the clinical stage. This is contradictory to its role of tumor suppressor. Here, we conducted a systematic analysis to elucidate whether there was other potential biological significance of RBM10 deficiency during the progression of LUAD.Materials and MethodsThe whole exome sequencing data of 39 tumor samples from early-stage LUADs (GGN cohort) and genomic and transcriptome data of the Cancer Genome Atlas (TCGA) LUAD cohort (TCGA_LUAD cohort) and a Chinese LUAD cohort (CHOICE_ADC cohort) were first obtained. Systematic bioinformatic analyses were then conducted to determine gene expression signature, immune infiltration levels and predicted immunotherapy response. Immunohistochemistry (IHC) was also conducted to validate the result of immune infiltration.ResultsThe mutation rate of RBM10 was significantly higher in the GGN cohort than that in the TCGA_LUAD and CHOICE_ADC cohorts. In both TCGA_LUAD and CHOICE_ADC cohorts, multiple immune related pathways were markedly enriched in RBM10 deficient group. Further analyses showed that tumors with RBM10 mutations displayed higher TMB, and LUADs with RBM10 deficiency also showed higher HLA expression levels, including many HLA class I and II molecules. Additionally, many immune cells, including myeloid dendritic cells, macrophages, neutrophils and CD8+T cells, showed higher infiltration levels in LUADs with RBM10 deficiency. Finally, some immune checkpoint molecules, such as PD-L1 and TIM-3, were highly expressed in RBM10 deficient population and the predicted immunotherapy response was calculated through TIDE algorithm, showing that IFNG expression, MSI score and CD8 expression were higher in RBM10 deficient group, while MDSC and M2 macrophage were lower in RBM10 deficient group.ConclusionOur study demonstrates that RBM10 deficient LUADs show higher HLA expression and immune cell infiltration, and some immune checkpoint molecules are also highly expressed. In brief, RBM10 deficiency could enhance anti-tumor immunity in LUAD.

Harnessing DNA replication stress to target RBM10 deficiency in lung adenocarcinoma

“…Intriguingly, a previous report showed that RBM10 deficiency in LUAD is associated with enriched immune pathways, elevated tumor mutational burden, and increased human leukocyte antigens (HLA) expression, suggesting that RBM10 deficiency may enhance anti-tumor immunity in LUAD 88 . In agreement with this, our RBM10 transcriptome in HCC827 and H1299 cell lines showed that RBM10 depletion leads to increased expression of proinflammatory cytokines such as IL1R2, TNFRSF1B, BMP2, IL7R and CCL2.…”

The genomic landscape of metastatic clear cell renal cell carcinoma after systemic therapy

“…RBM10 is an RNA binding protein known to be a TFEB fusion partner in MIT translocation‐associated RCC [ 26 ]. Somatic mutations in RBM10 have also been detected in NSCLC tumours and were found to be associated with increased influx of CD8+ T cells and IFN‐G transcriptional signatures [ 27 ]. Therefore, RBM10 and FBXW7 mutations may act as a biomarker in patients with ccRCC receiving immune checkpoint inhibitors.…”

RBM10 Is a Biomarker Associated with Pan-Cancer Prognosis and Immune Infiltration: System Analysis Combined with In Vitro and Vivo Experiments

“…A bioinformatics study found that in HCC, the RBM10 expression was positively correlated with infiltration of CD8 + T cell, as well as the expression of PD-1 and PD-L1 [8]. However, a recent report showed that CD8+ T cells showed a higher level of infiltration in LUAD with RBM10 deletion [16]. In this study, we found that the RBM10 expression was negatively correlated with B cells, CD8+ T cells, neutrophils, macrophages, and DC cell infiltration levels in most tumor types, indicating that RBM10 was likely to affect tumor development and prognosis by impacting the tumor microenvironment.…”

“…The study by Pang et al [8] have shown that the high RBM10 expression is positively linked with most immune cell infiltrates and the expressions of PD-1 and PD-L1 in hepatocellular carcinoma (HCC). In addition, a recent research confirms that the low RBM10 expression significantly increases the immune activity of LUAD and is negatively linked with CD8+ T cells having a tumorsuppressive effect, which makes it evident that RBM10 is linked with immune infiltration [16]. Most current studies about the role of RBM10 in cancer have been focused on an individual or limited to some specific tumor types.…”