Immunotherapy resistance in esophageal cancer: Possible mechanisms and clinical implications

Fang, Pinhao; Zhou, Jianfeng; Liang, Zhiwen; Yang, Yu‐Shang; Luan, Siyuan; Xiao, Xin; Li, Xiaokun; Zhang, Hanlu; Shang, Qi‐Xin; Zeng, Xiaoxi; Yuan, Yong

doi:10.3389/fimmu.2022.975986

Cited by 28 publications

(20 citation statements)

References 158 publications

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“…Esophageal cancer, characterized by high incidence and mortality rates, has limited success with traditional treatment methods [17]. Immunotherapy, as an emerging treatment approach including targeted therapies against speci c immune checkpoints and improved cellular therapies (such as CAR-T cell therapy), has shown potential in treating esophageal cancer, yet there remains a signi cant gap compared to meeting clinical needs [18,19]. To enhance the e cacy of immunotherapy, it is necessary to gain a deeper understanding of the immune microenvironment and tumor heterogeneity of esophageal cancer, thoroughly investigate its underlying mechanisms, and explore the reasons for immune suppression to identify new effective targets.…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Clinical characterization and immunosuppressive regulation of DNAJCB5B in Esophageal Squamous Cell Carcinoma

Hu,

Xu,

Tian

et al. 2024

Preprint

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Background DnaJ Homolog Subfamily C Member 5B (DNAJC5B), as a member of the heat shock protein family, has not yet been fully clarified in its role in tumor development, making it particularly important to study its potential role in the immunotherapy of esophageal cancer. Methods This study utilized the esophageal cancer dataset from the TCGA database, selecting genes associated with DNAJC5B expression through Pearson correlation analysis, followed by Gene Ontology (GO) functional enrichment analysis and KEGG pathway analysis. Additionally, single-cell RNA sequencing data was used to analyze DNAJC5B expression in different T cell subgroups. The prognostic value of DNAJC5B was evaluated using Kaplan-Meier survival curves, receiver operating characteristic (ROC) curves, and Cox proportional hazards model analysis. Results DNAJC5B is highly expressed in patients with advanced esophageal cancer, especially in males. Immunohistochemical staining results indicate a notable enrichment of DNAJC5B in the cytoplasm of cancer tissue cells. GO and KEGG analysis indicated significant correlations between DNAJC5B expression and immune-related processes like adaptive immune response and cell surface receptor signaling pathways. Single-cell analysis showed that DNAJC5B predominantly accumulates in CD8+ T cells and is associated with cell activation state. Survival analysis indicated that patients with high DNAJC5B expression had a median survival of 681 days, markedly lower than the 1361 days in those with low expression. Both univariate and multivariate Cox proportional hazards model analyses identified DNAJC5B as an independent prognostic factor in ESCC patients. Conclusion This study suggests that DNAJC5B may play a significant immunomodulatory role in esophageal cancer, particularly in regulating CD8+ T cell function and tumor immune escape. These findings support the potential of DNAJC5B as a biomarker for treatment and prognosis evaluation in esophageal cancer, providing new strategic directions for immunotherapy of esophageal cancer.

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Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Clinical characterization and immunosuppressive regulation of DNAJCB5B in Esophageal Squamous Cell Carcinoma

Hu,

Xu,

Tian

et al. 2024

Preprint

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“…In early-stage tumors, TGF-β exerts anti-tumor effects by promoting cell cycle arrest and apoptosis, while in advanced-stage tumors TGF-β promotes tumor metastasis and recurrence by promoting immunosuppression, promoting tumor angiogenesis, and inducing epithelial-mesenchymal transition (EMT) ( 119 ). TGF-β can directly activate Tregs to inhibit the cytotoxicity of CTLs and NK cell as well as the antigen-presenting function of APCs ( 120 ). And TGF-β can stimulate the transformation of fibroblasts into CAFs, thereby promoting the immune escape of tumor cells ( 121 ).…”

Section: Non-cellular Componentsmentioning

confidence: 99%

“…Over the past decade, ICIs has been successfully applied in the clinical practice as a novel therapy for treating ESCC, bringing new hope to ESCC patients. However, the overall response rate in patients with ESCC is lower than 30%, and the majority of patients initially treated with ICIs are likely to develop acquired resistance over time ( 120 ). The efficiency and durability of ICIs were greatly weakened by immunosuppression.…”

Section: Icis Drug Resistance and Tmementioning

confidence: 99%

“…Several ongoing clinical trials (NCT04732494, NCT04140500, NCT03708328) combining anti-PD-1 and anti-TIGIT/TIM/LAG-3 treatment as novel immunotherapies are expected to provide better prognosis for ESCC patients. In addition to inhibitory molecules expression, ESCC cells could develop drug resistance by secreting immunosuppressive cytokines and growth factors ( 120 ). Previous studies have demonstrated that T cells activated by ICIs therapy preferentially recognize mutant antigens ( 172 ).…”

Section: Icis Drug Resistance and Tmementioning

confidence: 99%

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Immune evasion in esophageal squamous cell cancer: From the perspective of tumor microenvironment

Huang

Tian

et al. 2023

Front. Oncol.

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Esophageal cancer (EC) is one of the most life-threatening malignancies worldwide. Esophageal squamous cell carcinoma (ESCC) is the dominant subtype, accounting for approximately 90% of new incident EC each year. Although multidisciplinary treatment strategies have advanced rapidly, patients with ESCC are often diagnosed at advanced stage and the long-term prognosis remains unsatisfactory. In recent decades, immunotherapy, such as immune checkpoint inhibitors (ICIs), tumor vaccines, and chimeric antigen receptor T-cell (CAR-T) therapy, has been successfully used in clinical practice as a novel therapy for treating tumors, bringing new hope to ESCC patients. However, only a small fraction of patients achieved clinical benefits due to primary or acquired resistance. Immune evasion plays a pivotal role in the initiation and progression of ESCC. Therefore, a thorough understanding of the mechanisms by which ESCC cells escape from anti-tumor immunity is necessary for a more effective multidisciplinary treatment strategy. It has been widely recognized that immune evasion is closely associated with the crosstalk between tumor cells and the tumor microenvironment (TME). TME is a dynamic complex and comprehensive system including not only cellular components but also non-cellular components, which influence hallmarks and fates of tumor cells from the outside. Novel immunotherapy targeting tumor-favorable TME represents a promising strategy to achieve better therapeutic responses for patients with ESCC. In this review, we provide an overview of immune evasion in ESCC, mainly focusing on the molecular mechanisms that underlie the role of TME in immune evasion of ESCC. In addition, we also discuss the challenges and opportunities of precision therapy for ESCC by targeting TME.

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“…Immunotherapy has been successfully applied in clinical practice as a novel therapeutic approach; however, there are problems, including low response rates, acquired resistance, and immune-related adverse events [4]. Furthermore, owing to the heterogeneity within the immune microenvironment and various oncological characteristics, the exact mechanism of immunotherapeutic refractory remains unclear [4]. Therefore, evaluating the tumor microenvironment (TME) is vital for achieving better therapeutic e cacy [5].…”

Section: Introductionmentioning

confidence: 99%

PD-L1-expressing cancer-associated fibroblasts induce tumor immunosuppression and contribute to poor clinical outcome

Kawasaki

Noma

Kato

et al. 2023

Preprint

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The programmed cell death 1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays a crucial role in tumor immune suppression, while the cancer-associated fibroblasts (CAFs) have various tumor-promoting functions. To determine the advantage of immunotherapy, the relationship between the cancer cells and the CAFs was evaluated in terms of the PD-1/PD-L1 axis. Overall, 140 cases of esophageal cancer underwent an immunohistochemical analysis of the PD-L1 expression and its association with the expression of the α smooth muscle actin (SMA), fibroblast activation protein (FAP), and the CD8, and forkhead box P3 (FoxP3) cells. The relationship between the cancer cells and the CAFs was evaluated in vitro, and the effect of the anti-PD-L1 antibody was evaluated using a syngeneic mouse model. A survival analysis showed that the PD-L1+ CAF group had worse survival than the PD-L1- group. In vitro and in vivo, direct interaction between the cancer cells and the CAFs showed a mutually upregulated PD-L1 expression. In vivo, the anti-PD-L1 antibody increased the number of dead CAFs and cancer cells, resulting in increased CD8+ T cells and decreased FoxP3 + regulatory T cells. We demonstrated that the PD-L1-expressing CAFs lead to poor outcomes in patients with esophageal cancer. The cancer cells and the CAFs mutually enhanced the PD-L1 expression and induced tumor immunosuppression. Therefore, the PD-L1-expressing CAFs may be good targets for cancer therapy, inhibiting tumor progression and improving host tumor immunity.

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Immunotherapy resistance in esophageal cancer: Possible mechanisms and clinical implications

Cited by 28 publications

References 158 publications

WITHDRAWN: Clinical characterization and immunosuppressive regulation of DNAJCB5B in Esophageal Squamous Cell Carcinoma

WITHDRAWN: Clinical characterization and immunosuppressive regulation of DNAJCB5B in Esophageal Squamous Cell Carcinoma

Immune evasion in esophageal squamous cell cancer: From the perspective of tumor microenvironment

PD-L1-expressing cancer-associated fibroblasts induce tumor immunosuppression and contribute to poor clinical outcome

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