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Prognosis of Non-small-cell Lung Cancer Patients With Lipid Metabolism Pathway Alternations to Immunotherapy.

ABSTRACT: Immune checkpoint inhibitors (ICIs) significantly improve the survival of patients with non-small-cell lung cancer (NSCLC), but only some patients obtain clinical benefits. Predictive biomarkers for ICIs can accurately identify people who will benefit from immunotherapy. Lipid metabolism signaling plays a key role in the tumor microenvironment (TME) and immunotherapy. Hence, we aimed to explore the association between the mutation status of the lipid metabolism pathway and the prognosis of patients with NSCLC treated with ICIs. We downloaded the mutation data and clinical data of a cohort of patients with NSCLC who received ICIs. Univariate and multivariate Cox regression models were used to analyze the association between the mutation status of the lipid metabolism signaling and the prognosis of NSCLC receiving ICIs. Additionally, The Cancer Genome Atlas (TCGA)-NSCLC cohort was used to explore the relationships between the different mutation statuses of lipid metabolism pathways and the TME. Additionally, we found that patients with high numbers of mutations in the lipid metabolism pathway had significantly enriched macrophages (M0- and M1-type), CD4 + T cells (activated memory), CD8 + T cells, Tfh cells and gamma delta T cells, significantly increased expression of inflammatory genes [interferon-γ (IFNG), CD8A, GZMA, GZMB, CXCL9, and CXCL10] and enhanced immunogenic factors [neoantigen loads (NALs), tumor mutation burden (TMB), and DNA damage repair pathways]. In the local-NSCLC cohort, we found that the group with a high number of mutations had a significantly higher tumor mutation burden (TMB) and PD-L1 expression. High mutation status in the lipid metabolism pathway is associated with significantly prolonged progression-free survival (PFS) in NSCLC, indicating that this marker can be used as a predictive indicator for patients with NSCLC receiving ICIs.

SUBMITTER: Cheng T

PROVIDER: S-EPMC8317604 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:As many as 30% of the patients with non-small cell lung cancer harbor oncogenic KRAS mutations, which leads to extensive remodeling of the tumor immune microenvironment. Although co-mutations in several genes have prognostic relevance in KRAS-mutated patients, their effect on tumor immunogenicity are poorly understood. In the present study, a total of 189 patients with non-small cell lung cancer underwent a standardized analysis including IHC, whole-exome DNA sequencing, and whole-transcriptome RNA sequencing. Patients with activating KRAS mutations demonstrated a significant increase in PDL1 expression and CD8+ T-cell infiltration. Both were increased in the presence of a co-occurring TP53 mutation and lost with STK11 co-mutation. Subsequent genomic analysis demonstrated that KRAS/TP53 co-mutated tumors had a significant decrease in the expression of glycolysis-associated genes and an increase in several genes involved in lipid metabolism, notably lipoprotein lipase, low-density lipoprotein receptor, and LDLRAD4. Conversely, in the immune-excluded KRAS/STK11 co-mutated group, we observed diminished lipid metabolism and no change in anaerobic glycolysis. Interestingly, in patients with low expression of lipoprotein lipase, low-density lipoprotein receptor, or LDLRAD4, KRAS mutations had no effect on tumor immunogenicity. However, in patients with robust expression of these genes, KRAS mutations were associated with increased immunogenicity and associated with improved overall survival. Our data further suggest that the loss of STK11 may function as a metabolic switch, suppressing lipid metabolism in favor of glycolysis, thereby negating KRAS-induced immunogenicity. Hence, this concept warrants continued exploration, both as a predictive biomarker and potential target for therapy in patients receiving ICI-based immunotherapy.SignificanceIn patients with lung cancer, we demonstrate that KRAS mutations increase tumor immunogenicity; however, KRAS/STK11 co-mutated patients display an immune-excluded phenotype. KRAS/STK11 co-mutated patients also demonstrated significant downregulation of several key lipid metabolism genes, many of which were associated with increased immunogenicity and improved overall survival in KRAS-mutated patients. Hence, alteration to lipid metabolism warrants further study as a potential biomarker and target for therapy in patients with KRAS-mutated lung cancer.

Project description:BACKGROUND:Increasing evidence has demonstrated the functional relevance of long non-coding RNAs (lncRNAs) to immunity regulation and the tumor microenvironment in non-small cell lung cancer (NSCLC). However, tumor immune infiltration-associated lncRNAs and their value in improving clinical outcomes and immunotherapy remain largely unexplored. METHODS:We developed a computational approach to identify an lncRNA signature (TILSig) as an indicator of immune cell infiltration in patients with NSCLC through integrative analysis for lncRNA, immune and clinical profiles of 115 immune cell lines, 187 NSCLC cell lines and 1533 patients with NSCLC. Then the influence of the TILSig on the prognosis and immunotherapy in NSCLC was comprehensively investigated. RESULTS:Computational immune and lncRNA profiling analysis identified an lncRNA signature (TILSig) consisting of seven lncRNAs associated with tumor immune infiltration. The TILSig significantly stratified patients into the immune-cold group and immune-hot group in both training and validation cohorts. These immune-hot patients exhibit significantly improved survival outcome and greater immune cell infiltration compared with immune-cold patients. Multivariate analysis revealed that the TILSig is an independent predictive factor after adjusting for other clinical factors. Further analysis accounting for TILSig and immune checkpoint gene revealed that the TILSig has a discriminatory power in patients with similar expression levels of immune checkpoint genes and significantly prolonged survival was observed for patients with low TILSig and low immune checkpoint gene expression implying a better response to immune checkpoint inhibitor (ICI) immunotherapy. CONCLUSIONS:Our finding demonstrated the importance and value of lncRNAs in evaluating the immune infiltrate of the tumor and highlighted the potential of lncRNA coupled with specific immune checkpoint factors as predictive biomarkers of ICI response to enable a more precise selection of patients.

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Prognosis of Non-small-cell Lung Cancer Patients With Lipid Metabolism Pathway Alternations to Immunotherapy.

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