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Like a Rolling Stone: Sting-Cgas Pathway and Cell-Free DNA as Biomarkers for Combinatorial Immunotherapy.

ABSTRACT: Combining immune checkpoint inhibitors with other treatments likely to harness tumor immunity is a rising strategy in oncology. The exact modalities of such a combinatorial regimen are yet to be defined, and most attempts have relied so far on concomitant dosing, rather than sequential or phased administration. Because immunomodulating features are likely to be time-, dose-, and-schedule dependent, the need for biomarkers providing real-time information is critical to better define the optimal time-window to combine immune checkpoint inhibitors with other drugs. In this review, we present the various putative markers that have been investigated as predictive tools with immune checkpoint inhibitors and could be used to help further combining treatments. Whereas none of the current biomarkers, such as the PDL1 expression of a tumor mutational burden, is suitable to identify the best way to combine treatments, monitoring circulating tumor DNA is a promising strategy, in particular to check whether the STING-cGAS pathway has been activated by cytotoxics. As such, circulating tumor DNA could help defining the best time-window to administrate immune checkpoint inhibitors after that cytotoxics have been given.

SUBMITTER: Sicard G

PROVIDER: S-EPMC7464249 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Like a Rolling Stone: Sting-Cgas Pathway and Cell-Free DNA as Biomarkers for Combinatorial Immunotherapy.

Sicard Guillaume G Fina Frédéric F Fanciullino Raphaelle R Barlesi Fabrice F Ciccolini Joseph J

Pharmaceutics 20200811 8

Combining immune checkpoint inhibitors with other treatments likely to harness tumor immunity is a rising strategy in oncology. The exact modalities of such a combinatorial regimen are yet to be defined, and most attempts have relied so far on concomitant dosing, rather than sequential or phased administration. Because immunomodulating features are likely to be time-, dose-, and-schedule dependent, the need for biomarkers providing real-time information is critical to better define the optimal t ...[more]

PMID: 32796670

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Project description:BackgroundThe 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.MethodsWe 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.ResultsIn 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.ConclusionsThe 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.

Dataset Information

Like a Rolling Stone: Sting-Cgas Pathway and Cell-Free DNA as Biomarkers for Combinatorial Immunotherapy.

Publications

Like a Rolling Stone: Sting-Cgas Pathway and Cell-Free DNA as Biomarkers for Combinatorial Immunotherapy.

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