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Significantly different immunoscores in lung adenocarcinoma and squamous cell carcinoma and a proposal for a new immune staging system.

ABSTRACT: TNM stage is not enough to accurately predict the prognosis of patients with non-small cell lung cancer (NSCLC). This study aimed to establish the Immunoscore (IS) in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), separately, and propose a new staging system in NSCLC. We used the multiplex fluorescent immunohistochemistry (mIHC) technology to detect 17 immune biomarkers of 304 patients with NSCLC. The LASSO-COX regression model was used to establish the IS_NSCLC in the training cohorts. The IS_NSCLC was then validated in the validation cohort. The constructed IS_LUAD contained three immune features: CD4⁺CD73⁺ _{core of tumor (CT)}, PD-L1⁺ _CT, and IDO⁺ _{invasive margin (IM)}. IS_LUSC also contained two immune features: CD8⁺CD39^-CD73^- _CT, CD8⁺Tim-3⁺ _IM. In the training cohort, significant prognostic differences were found upon comparing low-IS_NSCLC patients with high-IS_NSCLC patients. For LUAD, the 5-y disease-free survival (DFS) rates were 54.7% vs. 8.1% and the 5-y overall survival (OS) rates were 82.4% vs. 36% (all P< .0001). For LUSC, the 5-y DFS rates were 74.0% vs. 14.7% and the 5-y OS rates were 78.2% vs. 17.6% (all P< .0001). Multivariate analyses indicated that IS_NSCLC was an independent indicator for prognosis. Finally, we combined IS_NSCLC with clinicopathological factors to establish a TN-I staging system and two nomogram models for clinical use. The TN-I stage had better prediction accuracy than TNM stage. The newly established IS_LUAD and IS_LUSC were completely different, and both were excellent indicators for the prognostic prediction. The TN-I stage could effectively improve prognostic accuracy and facilitate clinical application. Abbreviations NSCLC, non-small cell lung cancer; IS, Immunoscore; mIHC, multiplex fluorescent immunohistochemistry; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; CT, core of tumor; IM, invasive margin; DFS, disease-free survival; OS, overall survival; SITC, the Society for Immunotherapy of Cancer; FFPE, formalin-fixed paraffin-embedded; MWT, microwave treatment; DCA, decision curve analysis; ROC, receiver operating characteristic; AUC, area under the curve; EGFR, epidermal growth factor receptor.

SUBMITTER: Zeng Z

PROVIDER: S-EPMC7553570 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Accumulating evidence indicates that immunotherapy helped to improve the survival and quality-of-life of patients with lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC) besides chemotherapy and gene targeting treatment. This study aimed to develop immune-related gene signatures in LUAD and LUSC subtypes, respectively. LUAD and LUSC samples were divided into high- and low-abundance groups of immune cell infiltration (Immunity_H and Immunity_L) based on the abundance of immune cell infiltrations. The distribution of immune cells was significantly different between the high- and low-immunity subtypes in LUAD and LUSC samples. The differentially expressed genes (DEGs) between those two groups in LUAD and LUSC contain some key immune-related genes, such as PDL1, PD1, CTLA-4, and HLA families. The DEGs were enriched in multiple immune-related pathways. Furthermore, the seven-immune-related-gene-signature (CD1B, CHRNA6, CLEC12B, CLEC17A, CLNK, INHA, and SLC14A2) prognostic model-based high- and low-risk groups were significantly associated with LUAD overall survival and clinical characteristics. The eight-immune-related-gene-signature (C4BPB, FCAMR, GRAPL, MAP1LC3C, MGC2889, TRIM55, UGT1A1, and VIPR2) prognostic model-based high- and low-risk groups were significantly associated with LUSC overall survival and clinical characteristics. The prognostic models were tested as good ones by receiver operating characteristic, principal component analysis, univariate and multivariate analysis, and nomogram. The verifications of these two immune-related-gene-signature prognostic models showed consistency in the train and test cohorts of LUAD and LUSC. In addition, patients with LUAD in the low-risk group responded better to immunotherapy than those in the high-risk group. This study revealed two reliable immune-related-gene-signature models that were significantly associated with prognosis and tumor microenvironment cell infiltration in LUAD and LUSC, respectively. Evaluation of the integrated characterization of multiple immune-related genes and pathways could help to predict the response to immunotherapy and monitor immunotherapy strategies.

Project description:BackgroundCancer stem cells (CSCs) refer to cells with self-renewal capability in tumors. CSCs play important roles in proliferation, metastasis, recurrence, and tumor heterogeneity. This study aimed to identify immune-related gene-prognostic models based on stemness index (mRNAsi) in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), respectively.MethodsX-tile software was used to determine the best cutoff value of survival data in LUAD and LUSC based on mRNAsi. Tumor purity and the scores of infiltrating stromal and immune cells in lung cancer tissues were predicted with ESTIMATE R package. Differentially expressed immune-related genes (DEIRGs) between higher- and lower-mRNAsi subtypes were used to construct prognostic models.ResultsmRNAsi was negatively associated with StromalScore, ImmuneScore, and ESTIMATEScore, and was positively associated with tumor purity. LUAD and LUSC samples were divided into higher- and lower-mRNAsi groups with X-title software. The distribution of immune cells was significantly different between higher- and lower-mRNAsi groups in LUAD and LUSC. DEIRGs between those two groups in LUAD and LUSC were enriched in multiple cancer- or immune-related pathways. The network between transcriptional factors (TFs) and DEIRGs revealed potential mechanisms of DEIRGs in LUAD and LUSC. The eight-gene-signature prognostic model (ANGPTL5, CD1B, CD1E, CNTFR, CTSG, EDN3, IL12B, and IL2)-based high- and low-risk groups were significantly related to overall survival (OS), tumor microenvironment (TME) immune cells, and clinical characteristics in LUAD. The five-gene-signature prognostic model (CCL1, KLRC3, KLRC4, CCL23, and KLRC1)-based high- and low-risk groups were significantly related to OS, TME immune cells, and clinical characteristics in LUSC. These two prognostic models were tested as good ones with principal components analysis (PCA) and univariate and multivariate analyses. Tumor T stage, pathological stage, or metastasis status were significantly correlated with DEIRGs contained in prognostic models of LUAD and LUSC.ConclusionCancer stemness was not only an important biological process in cancer progression but also might affect TME immune cell infiltration in LUAD and LUSC. The mRNAsi-related immune genes could be potential biomarkers of LUAD and LUSC. Evaluation of integrative characterization of multiple immune-related genes and pathways could help to understand the association between cancer stemness and tumor microenvironment in lung cancer.

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Significantly different immunoscores in lung adenocarcinoma and squamous cell carcinoma and a proposal for a new immune staging system.

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