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Radiation Therapy Promotes Hepatocellular Carcinoma Immune Cloaking via PD-L1 Upregulation Induced by cGAS-STING Activation.
- Source :
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International Journal of Radiation Oncology, Biology, Physics . Apr2022, Vol. 112 Issue 5, p1243-1255. 13p. - Publication Year :
- 2022
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Abstract
- <bold>Purpose: </bold>Radiation therapy (RT) is one of the main treatments for patients with unresectable hepatocellular carcinoma (HCC). Emerging evidence indicates that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) stimulator of interferon gene (STING) pathway is crucial in RT-induced antitumor immune responses. Here, we discovered that activation of the cancer cell-intrinsic cGAS-STING pathway mediated immune cloaking after RT-induced DNA damage.<bold>Methods and Materials: </bold>Key regulatory proteins in the cGAS-STING signaling pathway in human and murine HCC cell lines were knocked out or down using CRISPR and CRISPR-associated protein 9 or small interfering RNA. The underlying mechanism of immune cloaking and clinical significance of cGAS-STING-induced programmed cell death ligand 1 (PD-L1) expression were studied with both ex vivo analyses and in vitro experiments.<bold>Results: </bold>RT upregulated PD-L1 in patients with HCC, which correlated with poor survival. RT activated cGAS-STING, increasing immune-checkpoint PD-L1 expression in human and mouse liver cancer cells. Ionizing radiation activated the STING-TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) innate immune pathway, leading to PD-L1 upregulation in HCC cells and inhibiting cytotoxic T-lymphocyte activity and protecting tumor cells from immune-mediated eradication. Knockdown of cGAS, STING, TBK1, and IRF3 reversed the antitumor effect of cytotoxic T-lymphocyte-mediated cytotoxicity after ionizing radiation in vitro or in vivo. RT potentiated the antitumor effect of programmed cell death protein 1 and PD-L1 axis blockade and augmented cytotoxic T-cell (CTL) infiltration in HCC tumors in immunocompetent mice. CD8 depletion compromised the synergetic antitumor effect of combined RT and anti-PD-L1 blockade, demonstrating that CD8+ CTLs are required for antitumor immunity induced by combination therapy.<bold>Conclusions: </bold>Our results identified an immune-cloaking mechanism for RT-activated, innate immune cGAS-STING and suggested that RT enhances HCC immunotherapy. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03603016
- Volume :
- 112
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- International Journal of Radiation Oncology, Biology, Physics
- Publication Type :
- Academic Journal
- Accession number :
- 155628000
- Full Text :
- https://doi.org/10.1016/j.ijrobp.2021.12.162