Dataset Information

Tertiary lymphoid structures predict the prognosis and immunotherapy response of cholangiocarcinoma.

ABSTRACT:

Introduction

Cholangiocarcinoma (CCA) is a malignant tumor of the biliary epithelium with a poor prognosis. The lack of biomarkers to predict therapeutic response and prognosis is one of the major challenges for CCA treatment. Tertiary lymphoid structures (TLS) provide a local and pivotal microenvironment for tumor immune responses. The prognostic value and clinical relevance of TLS in CCA remain unclear. We aimed to explore the characteristics and clinical significance of TLS in CCA.

Methods

We investigated the prognostic value and clinical relevance of TLS in CCA using a surgery cohort containing 471 CCA patients (cohort 1) and an immunotherapy cohort containing 100 CCA patients (cohort 2). Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining were used to evaluate the maturity of TLS. Multiplex IHC (mIHC) was employed to characterize the composition of TLS.

Results

Different maturity of TLS were observed in CCA tissue sections. Strong staining of the four-gene signature including PAX5, TCL1A, TNFRSF13C, and CD79A were found in TLS regions. A high density of intra-tumoral TLS (T-score high) were significantly correlated with longer overall survival (OS) both in CCA cohort 1 (p = 0.002) and cohort 2 (p = 0.01), whereas a high density of peri-tumoral TLS (P-score high) were associated with shorter OS in these two cohorts (p = 0.003 and p = 0.03, respectively).

Conclusion

The established four-gene signature efficiently identified the TLS in CCA tissues. The abundance and spatial distribution of TLS were significantly correlated with the prognosis and immune checkpoint inhibitors (ICIs) immunotherapy response of CCA patients. The presence of intra-tumoral TLS are positive prognostic factors for CCA, which provide a theoretical basis for the future diagnosis and treatment of CCA.

SUBMITTER: Shang T

PROVIDER: S-EPMC10206168 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Tertiary lymphoid structures predict the prognosis and immunotherapy response of cholangiocarcinoma.

Shang Taiyu T Jiang Tianyi T Lu Tao T Wang Hui H Cui Xiaowen X Pan Yufei Y Xu Mengyou M Pei Mengmiao M Ding Zhiwen Z Feng Xiaofan X Lin Yunkai Y Li Xin X Tan Yexiong Y Feng Feiling F Dong Hui H Wang Hongyang H Dong Liwei L

Frontiers in immunology 20230510

<h4>Introduction</h4>Cholangiocarcinoma (CCA) is a malignant tumor of the biliary epithelium with a poor prognosis. The lack of biomarkers to predict therapeutic response and prognosis is one of the major challenges for CCA treatment. Tertiary lymphoid structures (TLS) provide a local and pivotal microenvironment for tumor immune responses. The prognostic value and clinical relevance of TLS in CCA remain unclear. We aimed to explore the characteristics and clinical significance of TLS in CCA.<h4 ...[more]

PMID: 37234171

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Project description:PurposeTo predict the tertiary lymphoid structures (TLSs) status and recurrence-free survival (RFS) of intrahepatic cholangiocarcinoma (ICC) patients using preoperative CT radiomics.Patients and methodsA total of 116 ICC patients were included (training: 86; external validation: 30). The enhanced CT images were performed for the radiomics model. The logistic regression analysis was applied for the clinical model. The combined model was based on the clinical and radiomics models.ResultsA total of 107 radiomics features were extracted, and after being eliminated and selected, six features were combined to establish a radiomics model for TLSs prediction. Arterial phase diffuse hyperenhancement and AJCC 8th stage were combined to construct a clinical model. The combined (radiomics nomogram) model outperformed both the independent radiomics model and clinical model in the training cohort (AUC, 0.85 vs. 0.82 and 0.75, respectively) and was validated in the external validation cohort (AUC, 0.88 vs. 0.86 and 0.71, respectively). Patients in the rad-score no less than -0.76 (low-risk) group showed significantly better RFS than those in the less than -0.76 (high-risk) group (p < 0.001, C-index = 0.678). Patients in the nomogram score no less than -1.16 (low-risk) group showed significantly better RFS than those of the less than -1.16 (high-risk) group (p < 0.001, C-index = 0.723).ConclusionsCT radiomics nomogram could serve as a preoperative biomarker of intra-tumoral TLSs status, better than independent radiomics or clinical models; preoperative CT radiomics nomogram achieved accurate stratification for RFS of ICC patients, better than the postoperative pathologic TLSs status.Critical relevance statementThe radiomics nomogram showed better performance in predicting TLSs than independent radiomics or clinical models and better prognosis stratification than postoperative pathologic TLSs status in ICC patients, which may facilitate identifying patients benefiting most from surgery and subsequent immunotherapy.Key points• The combined (radiomics nomogram) model consisted of the radiomics model and clinical model (arterial phase diffuse hyperenhancement and AJCC 8th stage). • The radiomics nomogram showed better performance in predicting TLSs than independent radiomics or clinical models in ICC patients. • Preoperative CT radiomics nomogram achieved more accurate stratification for RFS of ICC patients than the postoperative pathologic TLSs status.

Project description:BackgroundCholangiocarcinoma is a challenging malignancy with limited responses to conventional therapies, particularly immune checkpoint inhibitor therapy. Tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) are key components of the tumor microenvironment (TME) and have been implicated in the immune response to cancer. However, the role and difference of TLSs and TILs in patients with cholangiocarcinoma remains unclear. This study elucidates their contributions to the TME.MethodsWe examined 16 tumor samples from a single-arm, phase II trial of nivolumab plus modified gemcitabine and S-1 and various datasets. Immunohistochemistry and RNA sequencing were employed to assess TLSs and TILs presence and activity. Differential gene expression and signature of immune cell composition were examined by GeoMx Digital Spatial Profiler and Cancer Transcriptome Altas analysis.ResultsTLS-positive (N=7) patients demonstrated significantly better immunotherapy outcomes compared with TLS-negative (N=9) patients, including higher objective response rates (71% vs 0%) and disease control rates (100% vs 67%). The presence of TLSs correlated with improved progression-free and overall survival (p=0.03). TLSs were associated with "inflamed" tumors characterized by substantial immune infiltration, particularly involving T and B cells. Gene expression analyses identified significant upregulation of B cell-related genes in TLSs. Additionally, TLSs exhibited higher properties of memory B cells and myeloid dendritic cells but lower levels of innate immune cells compared with TILs. T cells within TLSs showed elevated expression of precursor-exhausted-related genes and lower cytotoxicity signature. Furthermore, TILs in TLS-positive tumors had higher levels of exhaustion signatures compared with TILs in TLS-negative tumors. Clinical data corroborated these findings, with higher PD-L1 and LAG-3 expression in TLS-positive tumors.ConclusionOur findings revealed that TILs in TLS-positive tumors have more exhausted T cell signature and PD-1 and LAG-3 protein expression in CCA which support our clinical finding. TLSs can predict favorable immunotherapy responses in patients with cholangiocarcinoma, highlighting their potential as a biomarker and therapeutic target to enhance treatment efficacy.

Dataset Information

Tertiary lymphoid structures predict the prognosis and immunotherapy response of cholangiocarcinoma.

Introduction

Methods

Results

Conclusion

Publications

Tertiary lymphoid structures predict the prognosis and immunotherapy response of cholangiocarcinoma.

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