Comprehensive landscape of resistance mechanisms for neoadjuvant therapy in esophageal squamous cell carcinoma by single-cell transcriptomics.
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ABSTRACT:
SUBMITTER: Yang Y
PROVIDER: S-EPMC10415278 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
Publications
Comprehensive landscape of resistance mechanisms for neoadjuvant therapy in esophageal squamous cell carcinoma by single-cell transcriptomics.
Yang Yushang Y Li Yanguo Y Yu Haopeng H Ding Zhenyu Z Chen Longqi L Zeng Xiaoxi X He Shunmin S Liao Qi Q Zhao Yi Y Yuan Yong Y
Signal transduction and targeted therapy 20230811 1
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Project description:Neoadjuvant therapy has been shown to improve survival for locally advanced esophageal squamous cell carcinoma (ESCC). However, some cases may acquire therapy resistance and the mechanism is still unclear. Here, we applied single-cell RNA sequencing on 7 ESCC patients with neoadjuvant therapy and 2 ESCC patients underwent general surgery alone to delineate the tumor heterogeneity, tumor microenvironment (TME) and potential hallmarks of therapy resistance. In total, 13 tumor cell lineages and its corresponding lineage-specific gene signatures, pathway activities, and transcription factors were identified, representing different mechanisms and hallmarks of neoadjuvant therapy resistance, such as oxidative stress response, hypoxia, DNA repair, ECM and EMT. Typically, tumor cell lineage Ep-C2 with signatures of oxidative stress response showed the strongest resistance to neoadjuvant therapy, particularly under chemoradiotherapy and immunotherapy combination. Excepting for the resistance mechanisms associated with tumor cell lineages, we also investigated three TME characteristics response to neoadjuvant therapy resistance, including the infiltration of cytotoxic-insufficient GZMK+ effector memory T cells, angiogenesis-promoting effect of myeloid lineages and the cell-cell communication of tumor-associated fibroblasts. These hallmarks of neoadjuvant therapy will help us to understand the therapy resistance in ESCC and provide important clues to identify potential targets to improve therapy sensitivity.
2023-08-14 | GSE221561 | GEO
Project description:Comprehensive Landscape of Resistance Mechanisms for Neoadjuvant Therapy in Esophageal Squamous Cell Carcinoma by single-cell Transcriptomics
| PRJNA914841 | ENA
Project description:BackgroundNeoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the most common approach for locally advanced resectable esophageal squamous cell carcinoma (ESCC) patients. How neoCRT impacts ESCC tumor immune microenvironment (TIME) has not been fully understood.MethodsSingle-cell RNA sequencing (scRNA-seq) was conducted to examine the neoCRT-driven cellular and molecular dynamics in 8 pre- and 7 post-neoCRT ESCC samples from 8 male patients.FindingsscRNA-seq data of about 112,000 cells were obtained. Expression programs of cell cycle, epithelium development, immune response, and extracellular structure in pre-treatment tumor cells were related to neoCRT response. Spearman correlation between CD8+ T cells' cytotoxicity and expression of checkpoint molecules was prominent in pre-neoCRT intermediate activated/exhausted CD8+ T cells. NeoCRT increased CD8+ T cells' infiltration but promoted their exhaustion in both major and minor responders. NeoCRT promoted differentiation of Th but demoted that of Treg cells in major responders. Maturation of cDC1s and expression of M2 macrophage markers increased while the number of cDC2s decreased after neoCRT. Higher activities of immune-related pathways in pre-neoCRT CD8+ T cells and macrophages, as well as a pronounced decrease of them after neoCRT, correlated with better neoCRT response. Interactions between intermediate activated/exhausted CD8+ T and macrophages, cDC1s, and LAMP3+ cDCs decreased after neoCRT.InterpretationOur comprehensive picture of the neoCRT-related immune changes provides deeper insights into immunological mechanisms associated with ESCC response to neoCRT, which may aid in future development of immune-strategies for improving ESCC treatment.FundingThis work was supported by the National Natural Science Foundation of China (82072607).
| S-EPMC9699982 | biostudies-literature
Project description:Esophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer-related mortality worldwide, with more than half of them occurred in China. Radiotherapy (RT) has been widely used for treating ESCC. However, radiation-induced DNA damage response (DDR) can promote the release of cytokines and chemokines, and triggers inflammatory reactions and changes in the tumor microenvironment (TME), thereby inhibiting the immune function and causing the invasion and metastasis of ESCC. Radioresistance is the major cause of disease progression and mortality in cancer, and it is associated with heterogeneity. Therefore, a better understanding of the radioresistance mechanisms may generate more reversal strategies to improve the cure rates and survival periods of ESCC patients. We mainly summarized the possible mechanisms of radioresistance in order to reveal new targets for ESCC therapy. Then we summarized and compared the current strategies to reverse radioresistance.
| S-EPMC10439611 | biostudies-literature
Project description:ImportanceThe association of neoadjuvant chemoimmunotherapy (NCIT) vs chemoradiotherapy (NCRT) with tumor downstaging and survival in locally advanced esophageal squamous cell carcinoma (ESCC) remains unclear because of limited evidence.ObjectiveTo compare the associations of NCIT and NCRT with tumor regression and long-term survival in patients with locally advanced ESCC.Design, setting, and participantsIn this comparative effectiveness research study, from January 2016 to March 2023, patients with locally advanced ESCC who underwent esophagectomy following NCRT or NCIT were identified from a prospective database of 8 high-volume esophageal surgery centers in China. Follow-up began on the date of surgery and continued until the last recorded contact or March 2024, whichever occurred first. Data were analyzed between April and September 2024.Main outcomes and measuresThe primary end points were 2-year overall survival (OS) and disease-free survival (DFS). Secondary end points included major pathologic response (MPR) and pathologic complete response (pCR). Cox proportional hazard regression analysis was used to investigate the risk factors for OS and DFS.ResultsThe study included 1428 patients (median [IQR] age, 63 [57-68] years; 1184 men [82.9%]), with 704 patients in the NCRT group and 724 patients in the NCIT group. After propensity score matching, there were 532 patients in each group. The 2-year OS (81.3% vs 71.3%; hazard ratio, 1.57; 95% CI, 1.26-1.96; P < .001) and DFS (73.9% vs 63.4%; hazard ratio, 1.37; 95% CI, 1.11-1.69; P < .001) rates were significantly higher in NCIT group than in the NCRT group. The NCRT group had a higher MPR rate than that of the NCIT group (71.8% vs 61.5%), whereas the pCR rates were similar (25.9% vs 22.9%). Multivariable Cox analysis demonstrated that NCIT and MPR were independently associated with both OS and DFS. The NCIT group exhibited a lower overall recurrence rate (126 patients [23.7%] vs 190 patients [35.7%]) and distant metastasis rate (72 patients [13.5%] vs 133 patients [25.0%]), although locoregional metastasis rates were similar (98 patients [18.4%] vs 111 patients [20.9%]). Better OS and DFS were obtained for the NCIT group than for the NCRT group, regardless of whether adjuvant immunotherapy was given.Conclusions and relevanceCompared with NCRT, patients with locally advanced ESCC receiving NCIT had better 2-year OS and DFS. The decrease in distant metastasis may be the main reason, but further prospective randomized clinical trials are needed to verify this finding.
| S-EPMC11923775 | biostudies-literature
Project description:BackgroundThe study purpose was to characterize the mycobiome and its associations with the expression of pathogenic genes in esophageal squamous cell carcinoma (ESCC).MethodsPatients with primary ESCC were recruited from two central hospitals. We performed internal transcribed spacer 1 (ITS1) ribosomal DNA sequencing analysis. We compared differential fungi and explored the ecology of fungi and the interaction of bacteria and fungi.ResultsThe mycobiota diversity was significantly different between tumors and tumor-adjacent samples. We further analysed the differences between the two groups, at the species level, confirming that Rhodotorula toruloides, Malassezia dermatis, Hanseniaspora lachancei, and Spegazzinia tessarthra were excessively colonized in the tumor samples, whereas Preussia persica, Fusarium solani, Nigrospora oryzae, Acremonium furcatum, Golovinomyces artemisiae, and Tausonia pullulans were significantly more abundant in tumor-adjacent samples. The fungal co-occurrence network in tumor-adjacent samples was larger and denser than that in tumors. Similarly, the more complex bacterial-fungal interactions in tumor-adjacent samples were also detected. The expression of mechanistic target of rapamycin kinase was positively correlated with the abundance of N. oryzae and T. pullulans in tumor-adjacent samples. In tumors, the expression of MET proto-oncogene, receptor tyrosine kinase (MET) had a negative correlation and a positive correlation with the abundance of R. toruloides and S. tessarthra, respectively.ConclusionThis study revealed the landscape of the esophageal mycobiome characterized by an altered fungal composition and bacterial and fungal ecology in ESCC.
| S-EPMC10147516 | biostudies-literature
Project description: Not available
| S-EPMC10944718 | biostudies-literature
Project description:ObjectiveThe aim of this study was to establish a liquid-biopsy assay to predict response to neoadjuvant therapy (NAT) in esophageal squamous cell carcinoma (ESCC) patients.Summary background dataPretreatment prediction of resistance to NAT is of great significance for the selection of treatment options in ESCC patients. In this study, we comprehensively translated tissue-based microRNA (miRNA) and messenger RNA (mRNA) expression biomarkers into a liquid biopsy assay.MethodsWe analyzed 186 clinical ESCC samples, which included 128 formalin-fixed paraffin-embedded and a matched subset of 58 serum samples, from 2 independent institutions. We performed quantitative reverse-transcription polymerase chain reaction, and developed a resistance-prediction model using the logistic regression analyses.ResultsWe first evaluated the potential of 4-miRNAs and 3-mRNAs panel, which robustly predicted resistance to NAT [area under the curve (AUC): 0.85]. Moreover, addition of tumor size to this panel increased predictive potential to establish a combination signature (AUC: 0.92). We successfully validated this signature performance in independent cohort, and our model was more accurate when the signature was combined with clinical predictors (AUC: 0.81) to establish a NAT resistance risk (NATRR) model. Finally, we successfully translated our NATRR model into a liquid biopsy assay (AUC: 0.78), and a multivariate regression analysis revealed this model as an independent predictor for response to NAT (odds ratio: 6.10; P < 0.01).ConclusionsWe successfully developed a liquid biopsy-based assay that allows robust prediction of response to NAT in ESCC patients, and our assay provides fundamentals of developing precision-medicine.
| S-EPMC9276630 | biostudies-literature
Project description:BackgroundImmunotherapy has achieved remarkable efficacy in treating oesophageal squamous cell carcinoma (ESCC). However, this treatment has limited efficacy in some patients. An increasing number of evidence suggested that immune cells within the tumour microenvironment (TME) are strongly related to immunotherapy response and patient prognosis. Thus, the landscape of immune cell infiltration (ICI) in ESCC needs to be mapped.MethodsIn the study, the ICI pattern in 206 cases of ESCC was characterised by two algorithms, namely, CIBERSORT and single-sample gene set enrichment analysis (ssGSEA). The ICI score of each specimen was calculated by principal component analysis (PCA) according to ICI signature genes A (ICISGA) and B (ICISGB). The prognostic difference was evaluated by using the Kaplan-Meier method. The related pathways of ICI score were investigated by applying gene set enrichment analysis (GSEA). The R packages of 'regplot', 'timeROC' and 'rms' were applied for the construction of nomogram model.ResultThree TME subtypes were identified with no prognostic implication. A total of 333 differentially expressed genes (DEGs) among immune subtypes were determined, among which ICISGA and ICISGB were identified. Finally, ICI scores were constructed, and the patients were grouped into high or low ICI score group. Compared with the low ICI score group, the high ICI score group had better prognosis. GSEA revealed that the high ICI score group referred to multiple signalling pathways, including B cell receptor, Fc gamma R-mediated phagocytosis, NOD-like receptor and TGF-β signalling pathways. In addition, the nomogram model was constructed to evaluate 1-, 3- and 5-year probability of death in an ESCC patient. The ROC and calibration curves indicated that the model has a good discrimination ability.ConclusionWe depicted a comprehensive ICI landscape in ESCC. ICI score may be used as a predictor of survival rate, which may be helpful for guiding immunotherapy in the future.
| S-EPMC9300817 | biostudies-literature
Project description:Immunotherapy provides durable responses for locally advanced esophageal carcinoma clinical therapy in numerous patients. However, the mechanisms of resistance to immunotherapy have not been elucidated. The phenomenon of the histological transformation of non-small cell lung cancer to small cell lung cancer resulting in resistance to immune checkpoint inhibitors (ICIs) has been reported. It remains unclear whether ICIs or chemotherapy could cause a similar transformation from esophageal squamous cell carcinoma (ESCC) to esophageal neuroendocrine carcinoma (ENEC). The present study report the case of a patient initially diagnosed with stage II ESCC who underwent radical surgery after three cycles of neoadjuvant therapy with cisplatin, albumin bound paclitaxel and ICIs. Immunohistochemical staining confirmed the absence of the SCC component and the presence of the NEC component, with negativity for CK5/6 and tumor protein p40, but positive expression of tumor protein p53, pan-cytokeratin, synaptophysin and CD56. The patient was followed up for 5 months with no treatment or postoperative complications. In conclusion, histological transformation to ENEC is a potential mechanism of acquired resistance to ICIs in ESCC. Prospective larger studies are warranted to further characterize ESCC-to-NEC transformation on use of ICIs.
| S-EPMC10928968 | biostudies-literature