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Prognostic Value of Tumor Mutational Burden Related to Immune Infiltration in Cervical Squamous Cell Carcinoma.

ABSTRACT: Cervical squamous cell carcinoma is one of the most common causes of female cancer deaths worldwide. At present, immunotherapy using immune checkpoint blockade (ICB) has improved the prognosis of many cancer patients, and neoantigens generated by mutations may serve as potential biomarkers for predicting the outcome of ICB therapy. In this study, we identified missense mutations as the most frequent in landscapes of gene mutation in cervical squamous cell carcinoma (CESC) samples. Patients with higher tumor mutation burden (TMB) presented higher overall survival (OS). In addition, there was a significant correlation between the high TMB group and fractions of most immune cells. Univariate and multivariate Cox regression analyses identified five hub genes (IFNG, SERPINA3, CCL4L2, TNFSF15, and IL1R1) that were used to build a prognostic model. In the prognostic model, the low-risk group achieved better OS. Mutations in the five hub genes mainly affected the infiltration level of CD8+ T cells and dendritic cells. In conclusion, our study is valuable for exploring the role of TMB and its relationship with immune infiltration in CESC. Moreover, the prognosis model may help predict the sensitivity of patients to immunotherapy and provide underlying biomarkers for personalized immunotherapy.

SUBMITTER: Wen F

PROVIDER: S-EPMC8631969 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Prognostic Value of Tumor Mutational Burden Related to Immune Infiltration in Cervical Squamous Cell Carcinoma.

Wen Fang F Ruan Shuai S Huang Wenjie W Chen Xiaoxue X Wang Yulan Y Gu Suping S Liu Jiatong J Liu Shenlin S Shu Peng P

Frontiers in medicine 20211111

Cervical squamous cell carcinoma is one of the most common causes of female cancer deaths worldwide. At present, immunotherapy using immune checkpoint blockade (ICB) has improved the prognosis of many cancer patients, and neoantigens generated by mutations may serve as potential biomarkers for predicting the outcome of ICB therapy. In this study, we identified missense mutations as the most frequent in landscapes of gene mutation in cervical squamous cell carcinoma (CESC) samples. Patients with ...[more]

PMID: 34859010

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Project description:BackgroundLung squamous cell carcinoma (LUSC) is a highly malignant tumor with an extremely poor prognosis. Immune checkpoint inhibitors (ICIs) improve survival in some patients with LUSC. Tumor mutation burden (TMB) is a useful biomarker to predict the efficacy of ICIs. However, predictive and prognostic factors related to TMB in LUSC remain elusive. This study aimed to find effective biomarkers based on TMB and immune response and establish a prognostic model of LUSC.MethodsWe downloaded Mutation Annotation Format (MAF) files from The Cancer Genome Atlas (TCGA) database and identified immune-related differentially expressed genes (DEGs) between high- and low-TMB groups. The prognostic model was established using cox regression. The primary outcome was overall survival (OS). Receiver operating characteristic (ROC) curves and calibration curves were used to verify the accuracy of the model. GSE37745 acted as external validation set. The expression and prognosis of hub genes as well as their correlation with immune cells and somatic copy number variation (sCNA) were analyzed.ResultsThe TMB of patients with LUSC was correlated with prognosis and stage. High TMB group had higher survival rate (P<0.001). Five TMB-related hub immune genes (TINAGL1, FGFR2, CTSE, SFTPA1, and IGHV7-81) were identified and the prognostic model was constructed. The survival time of high-risk group was significantly shorter than that of low-risk group (P<0.001). The validation results of the model were quite stable in different data sets, and the area under curve (AUC) of training set and validation set were 0.658 and 0.644, respectively. Calibration chart, risk curve, and nomogram revealed that the prognostic model was reliable in predicting the prognostic risk of LUSC, and the risk score of the model could be used as an independent prognostic factor for LUSC patients (P<0.001).ConclusionsOur results show that high TMB is associated with poor prognosis in patients with LUSC. The prognostic model related to TMB and immunity can effectively predict the prognosis of LUSC, and risk score is one of the independent prognostic factors of LUSC. However, this study still has some limitations, which need to be further verified in large-scale and prospective studies.

Project description:The host's immune system plays a pivotal role in many tumor types, including squamous cell carcinomas (SCCs). We aim to identify immunological prognosticators for lymph node metastases (LNM) and disease-specific survival (DSS) in penile SCC. For this retrospective observational cohort study, penile SCC patients (n?=?213) treated in the Netherlands Cancer Institute, were selected if sufficient formalin-fixed, paraffin-embedded tumor material was available. Analysis included previously described high-risk human papilloma virus (hrHPV) status, immunohistochemical scores for classical and non-classical human leukocyte antigen (HLA) class I, programmed death ligand-1 (PD-L1) expression, and novel data on tumor-infiltrating macrophages and cytotoxic an regulatory T-cells. Clinicopathological characteristics and extended follow-up were also included. Regression analyses investigated relationships of the immune parameters with LNM and DSS. In the total cohort, diffuse PD-L1 tumor-cell expression, CD163+ macrophage infiltration, non-classical HLA class I upregulation, and low stromal CD8+ T-cell infiltration were all associated with LNM. In the multivariable model, only tumor PD-L1 expression remained a significant predictor for LNM (odds ratio (OR) 2.8, p?=?0.05). hrHPV negativity and diffuse PD-L1 tumor-cell expression were significantly associated with poor DSS and remained so upon correction for clinical parameters [hazard ratio (HR) 9.7, p?<?0.01 and HR 2.8, p?=?0.03]. The only immune factor with different expression in HPV+ and HPV- tumors was PD-L1, with higher PD-L1 expression in the latter (p?=?0.03). In the HPV- cohort (n?=?158), LNM were associated with diffuse PD-L1 tumor-cell expression, high intratumoral CD163+ macrophage infiltration, and low number of stromal CD8+ T-cells. The first two parameters were also linked to DSS. In the multivariable regression model, diffuse PD-L1 expression remained significantly unfavorable for DSS (HR 5.0, p?<?0.01). These results emphasize the complexity of the tumor microenvironment in penile cancer and point toward several possible immunotherapy targets. Here described immune factors can aid risk-stratification and should be evaluated in clinical immunotherapy studies to ultimately lead to patient tailored treatment.

Dataset Information

Prognostic Value of Tumor Mutational Burden Related to Immune Infiltration in Cervical Squamous Cell Carcinoma.

Publications

Prognostic Value of Tumor Mutational Burden Related to Immune Infiltration in Cervical Squamous Cell Carcinoma.

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