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EBV enhances immunotherapy sensitivity in intrahepatic cholangiocarcinoma through cGAS-STING pathway activation
Lingli Huang1,2,3,4, Qian Zhong2,3,4,5, Silan Huang1,2,3,4
1VIP Department, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.
Background:
The absence of representative Epstein-Barr virus-associated intrahepatic cholangiocarcinoma (EBVaICC) cell lines has limited our understanding of the molecular and immunological characteristics of this cancer subtype.
Methods:
We reviewed patients with metastatic cholangiocarcinoma at Sun Yat-sen University Cancer Center from January 2015 to August 2023. Among them, 22 patients with EBVaICC and 66 patients with non-EBVaICC who received anti-PD1 treatment were included. Additionally, 2 EBV-positive ICC cell lines, RBE-EBV and HuH28-EBV, were developed through cell-to-cell infection. Stable EBV infection and responsiveness to viral reactivation were confirmed. Transcriptomic and bioinformatics analyses were performed, and in vitro experiments examined the immune effects of EBV-positive ICC. Key immune-related genes and cytokines were validated by reverse transcription quantitative polymerase chain reaction and ELISA in cell lines and patient plasma samples.
Results:
In this study, we found that patients with EBVaICC showed enhanced immune responses and improved overall and progression-free survival compared to patients with non-EBVaICC. We first successfully established and validated 2 EBV-positive ICC cell lines (RBE-EBV and HuH28-EBV). These cell lines were confirmed for stable EBV infection and displayed responsiveness to viral reactivation, making them suitable for future studies. Transcriptomic analyses and in vitro studies revealed that EBV activated the cGAS-STING pathway, resulting in MHC-I upregulation and CXCL10 secretion in ICC cells, which collectively enhanced CD8+ T cell chemotaxis and cytotoxicity. Furthermore, ELISA analysis showed higher plasma levels of CXCL10 and IFN-γ in patients with EBVaICC, suggesting a potential role for EBV in enhancing immunotherapy sensitivity in this subtype.
Conclusions:
The established EBV-positive ICC cell lines revealed enhanced immunogenicity driven by cGAS-STING pathway activation, providing valuable models for future research and insights into the mechanisms of improved immunotherapy sensitivity in EBVaICC.
Insights
New cell lines reveal Epstein-Barr virus-associated intrahepatic cholangiocarcinoma (EBVaICC) has enhanced immunogenicity. This discovery offers insights into improved immunotherapy sensitivity for EBVaICC patients.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Representative cell lines for Epstein-Barr virus-associated intrahepatic cholangiocarcinoma (EBVaICC) are lacking, hindering research into this cancer's molecular and immunological aspects.
- Understanding EBVaICC is crucial for developing targeted therapies and improving patient outcomes.
Purpose of the Study:
- To establish and validate novel EBV-positive intrahepatic cholangiocarcinoma (ICC) cell lines.
- To investigate the molecular and immunological mechanisms underlying EBVaICC.
- To explore the potential of EBV in enhancing immunotherapy response in ICC.
Main Methods:
- Retrospective review of metastatic cholangiocarcinoma patients treated with anti-PD1 therapy, including EBVaICC and non-EBVaICC cohorts.
- Development and validation of two EBV-positive ICC cell lines (RBE-EBV, HuH28-EBV) via cell-to-cell infection.
- Transcriptomic, bioinformatics, in vitro, RT-qPCR, and ELISA analyses to assess immune responses and EBV's role.
Main Results:
- Patients with EBVaICC demonstrated superior immune responses and improved survival outcomes compared to non-EBVaICC patients.
- Established EBV-positive ICC cell lines (RBE-EBV, HuH28-EBV) showed stable EBV infection and responsiveness to viral reactivation.
- EBV activation of the cGAS-STING pathway led to MHC-I upregulation and CXCL10 secretion, enhancing CD8+ T cell activity and suggesting increased immunotherapy sensitivity.
Conclusions:
- Novel EBV-positive ICC cell lines provide valuable models for studying EBVaICC.
- EBV-positive ICC exhibits enhanced immunogenicity via cGAS-STING pathway activation.
- Findings offer insights into mechanisms driving improved immunotherapy sensitivity in EBVaICC.
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