Dataset Information

Possible prediction of the response of esophageal squamous cell carcinoma to neoadjuvant chemotherapy based on gene expression profiling.

ABSTRACT:

Background

Heterogeneous efficacy of neoadjuvant chemotherapy has led to controversies that have limited its application in clinical practice. Thus, we aimed to identify potential biomarkers predicting esophageal squamous cell carcinoma (ESCC) chemo-responsiveness by gene expression profiling.

Methods

CCK8 assay was used to evaluate the growth inhibitory effect of different concentrations of cisplatin and paclitaxel on the ESCC cell lines EC109, KYSE450, KYSE410, KYSE510, and KYSE150 to differentiate between chemosensitive and chemoresistant cell lines. Gene expression profiling and Real-time PCR were applied to analyze and validate the gene expression differences between chemosensitive and chemoresistant cell lines. IHC was conducted to examine the expression of selected target markers MUC4, MUC13, and MUC20 in 186 ESCC resection samples and the relationships between their expression and tumor regression grade was analyzed. Moreover, RNAi was conducted to instantly block the expression of MUC4, MUC13, and MUC20 to observe their influences on chemo-responsiveness.

Results

EC109 was found to be relatively sensitive to both cisplatin and paclitaxel, while KYSE410 was relatively resistant to cisplatin, KYSE510 was relatively resistant to paclitaxel. Gene expression profiling analysis showed that 2018 genes were differentially expressed in sensitive cell line compared to resistant cell lines. The expression patterns of MUC4, MUC13, MUC20 were validated. Low expression of MUC4 and MUC20 in resection samples was significantly correlated with better TRG. Blockage of MUC20 and MUC13 decreased the drug-resistance capacity and chemosensitivity, respectively.

Conclusions

MUC4 and MUC20 were identified as potential biomarkers for predicting the efficacy of neoadjuvant chemotherapy in ESCC patients.

SUBMITTER: Shen LY

PROVIDER: S-EPMC4826224 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Publications

Possible prediction of the response of esophageal squamous cell carcinoma to neoadjuvant chemotherapy based on gene expression profiling.

Shen Lu-Yan LY Wang Hui H Dong Bin B Yan Wan-Pu WP Lin Yao Y Shi Qi Q Chen Ke-Neng KN

Oncotarget 20160101 4

<h4>Background</h4>Heterogeneous efficacy of neoadjuvant chemotherapy has led to controversies that have limited its application in clinical practice. Thus, we aimed to identify potential biomarkers predicting esophageal squamous cell carcinoma (ESCC) chemo-responsiveness by gene expression profiling.<h4>Methods</h4>CCK8 assay was used to evaluate the growth inhibitory effect of different concentrations of cisplatin and paclitaxel on the ESCC cell lines EC109, KYSE450, KYSE410, KYSE510, and KYSE ...[more]

PMID: 26673820

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Project description:BackgroundThe efficacy of neoadjuvant chemo-immunotherapy (NAT) in esophageal squamous cell carcinoma (ESCC) is challenged by the intricate interplay within the tumor microenvironment (TME). Unveiling the immune landscape of ESCC in the context of NAT could shed light on heterogeneity and optimize therapeutic strategies for patients.MethodsWe analyzed single cells from 22 baseline and 24 post-NAT treatment samples of stage II/III ESCC patients to explore the association between the immune landscape and pathological response to neoadjuvant anti-PD-1 combination therapy, including pathological complete response (pCR), major pathological response (MPR), and incomplete pathological response (IPR).ResultsSingle-cell profiling identified 14 major cell subsets of cancer, immune, and stromal cells. Trajectory analysis unveiled an interesting link between cancer cell differentiation and pathological response to NAT. ESCC tumors enriched with less differentiated cancer cells exhibited a potentially favorable pathological response to NAT, while tumors enriched with clusters of more differentiated cancer cells may resist treatment. Deconvolution of transcriptomes in pre-treatment tumors identified gene signatures in response to NAT contributed by specific immune cell populations. Upregulated genes associated with better pathological responses in CD8 + effector T cells primarily involved interferon-gamma (IFNγ) signaling, neutrophil degranulation, and negative regulation of the T cell apoptotic process, whereas downregulated genes were dominated by those in the immune response-activating cell surface receptor signaling pathway. Natural killer cells in pre-treatment tumors from pCR patients showed a similar upregulation of gene expression in response to IFNγ but a downregulation of genes in the neutrophil-mediated immunity pathways. A decreased cellular contexture of regulatory T cells in ESCC TME indicated a potentially favorable pathological response to NAT. Cell-cell communication analysis revealed extensive interactions between CCL5 and its receptor CCR5 in various immune cells of baseline pCR tumors. Immune checkpoint interaction pairs, including CTLA4-CD86, TIGIT-PVR, LGALS9-HAVCR2, and TNFSF4-TNFRSF4, might serve as additional therapeutic targets for ICI therapy in ESCC.ConclusionsThis pioneering study unveiled an intriguing association between cancer cell differentiation and pathological response in esophageal cancer patients, revealing distinct subgroups of tumors for which neoadjuvant chemo-immunotherapy might be effective. We also delineated the immune landscape of ESCC tumors in the context of clinical response to NAT, which provides clinical insights for better understanding how patients respond to the treatment and further identifying novel therapeutic targets for ESCC patients in the future.

Project description:BackgroundNeoadjuvant chemotherapy (NAC) has become the standard of care for resectable esophageal squamous cell carcinoma (ESCC) which is one of the most lethal cancers, to improve resectability and prognosis. On this basis, to provide individually optimized therapy for ESCC, a minimally-invasive biomarker for response to NAC is strongly desired. This study aimed to identify the miRNA signature in serum specimens taken from ESCC patients undergoing NAC through genome-wide microarray technology.MethodsComprehensive miRNA-expression profiles of serum specimens from ESCC patients before initial treatment were analyzed using microarray. A qPCR assay was performed to test the robustness of identified serum-based miRNA signature for discriminating response to NAC with serum specimens taken from 100 ESCC cases undergoing NAC.ResultsWe prioritized 62 miRNAs differentially expressed between responders and non-responders (absolute log2 fold change > 1.0, corresponding P < 0.05) and from the 62 miRNAs, we selected the miR-23a-5p, miR-193b-5p, and miR-873-3p, which were highly expressed in non-responders. Following qPCR analysis indicated the expression of miR-193b-5p and miR-873-3p in serum specimens were significantly higher in non-responders among three selected miRNAs (P = 0.004 and 0.001, respectively). Subsequently, we developed 2-miR-model (miR-193b-5p and miR-873-3p), 3-miR-model, and 2-miR + lymphatic invasion (ly) model based on logistic regression analysis, which achieved the better area under the receiver operating characteristic curves than those of single miRNAs as 2-miR-model, 0.70 (95% CI 0.57 to 0.82); 3-miR-model, 0.70 (95% CI 0.57 to 0.83); and 2-miR + ly, 0.73 (95% CI 0.60-0.86), respectively. Furthermore, we compared the detective power of the combined model: 2-miR + ly for discriminating non-responders to NAC, to other pretreatment clinical features. Consequently, 2-miR + ly model was superior to serum SCC antigen with great significance (P = 0.01) and to ly, and clinical T stage with marginal significance (P = 0.18, 0.07, respectively).ConclusionsCollectively, we demonstrated that the potential of a multi-miRNA biomarker for identifying NAC response in ESCC is realistic, and can be used in the clinic with the further validation.

Project description:ImportanceThe objective response (ORR) rate in patients with locally advanced hypopharyngeal squamous cell-carcinoma (LA-HPSCC) following neoadjuvant chemotherapy (NACT) of albumin-bound paclitaxel plus carboplatin is low. At present, it is unclear whether the addition of pembrolizumab could increase the ORR or not.ObjectiveTo investigate whether the addition of pembrolizumab could increase the ORR, and to develop a nomogram to predict the response of pembrolizumab addition.DesignRetrospective cohort study.SettingThis study was conducted at a single institution.ParticipantsThis study included 129 patients who conformed to the inclusion criteria.Intervention or exposuresNACT with or without pembrolizumab for patients with LA-HPSCC.Main outcome measuresThe ORR was analyzed according to the RECIST 1.1 criteria and a nomogram was developed based on least absolute shrinkage and selection operator and multivariable Cox regression analysis. Predictive accuracy and discriminative ability of the nomogram were evaluated by receiver operating characteristics, precision recall, calibration curves, and decision curve analysis.ResultsEighty-two patients received NACT and 47 also received pembrolizumab. ORR was higher in patients receiving additional pembrolizumab (66.0% vs 47.6%, χ2 = 4.074, P = .044). The nomogram identified pretreatment levels of lymphocytes and red blood cells as independent predictors of a high ORR, while basophil levels were an independent predictor of a low ORR. Calibration curve showed that the nomogram-based predictions corresponded well with actual observations. C-index of the nomogram was 0.925 (0.848-1.002) and the area under curve was 0.925. Decision curve analysis affirmed that the nomogram had important clinical value.Conclusions and relevancePembrolizumab could improve the ORR in LA-HPSCC patients treated with NACT. Furthermore, a risk-prediction nomogram incorporating readily assessable routine pretreatment blood parameters can accurately estimate the response to NACT with pembrolizumab, leading to precise treatment and minimizing the waste of medical resources.

Dataset Information

Possible prediction of the response of esophageal squamous cell carcinoma to neoadjuvant chemotherapy based on gene expression profiling.

Background

Methods

Results

Conclusions

Publications

Possible prediction of the response of esophageal squamous cell carcinoma to neoadjuvant chemotherapy based on gene expression profiling.

Similar Datasets

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