AI Article Synopsis
- The study examines the role of acid sphingomyelinase (ASMase) in the effectiveness of radiation therapy against tumors, highlighting its importance in tumor radiocurability and immune response.
- The researchers used Lewis Lung Carcinoma (LLC) cells in different mouse models to observe how ASMase affects tumor response to radiation, including immune cell infiltration and related signaling pathways.
- Findings revealed that ASMase is crucial for a successful immune response to radiation, as tumors in ASMase knockout mice did not respond effectively, underscoring the importance of ASMase in mediating radiation-induced anti-tumor immunity through STING activation.
Article Abstract
Background/aims: Tumor response to radiation is thought to depend on the direct killing of tumor cells. Our laboratory has called this into question. Firstly, we showed that the biology of the host, specifically the endothelial expression of acid sphingomyelinase (ASMase), was critical in determining tumor radiocurability. Secondly, we have shown that the immune system can enhance radiation response by allowing a complete tumor control in hemi-irradiated tumors. In this paper, we focus on the integration of these two findings.
Methods: We used Lewis Lung Carcinoma (LLC) cells, injected in the flank of either: (i) ASMase knockout or (ii) WT of matched background (sv129xBl/6) or (iii) C57Bl/6 mice. Radiation therapy (RT) was delivered to 50% or 100% of the LLC tumor volume. Tumor response, immune infiltration (CD8 T cells), ICAM-1, and STING activation were measured. Radiotherapy was also combined with methyl-cyclodextrin, to inhibit the ASMase-mediated formation of ceramide-enriched lipid rafts.
Results: We recapitulated our previous finding, namely that tumor hemi-irradiation was sufficient for tumor control in the LLC/C57Bl/6 model. However, in ASMase KO mice hemi-irradiation was ineffective. Likewise, pharmacological inhibition of ASMase significantly reduced the tumor response to hemi-irradiation. Further, we demonstrated elevated ICAM-1 expression, increased levels of CD8 T cells, ICAM-1, and STING activation in tumors growing in C57Bl/6 mice, as well as the ASMase WT strain. However, no such changes were seen in tumors growing in ASMase KO mice.
Conclusion: ASMase and ceramide generation are necessary to mediate a radiation-induced anti-tumor immune response STING activation.
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| http://dx.doi.org/10.33594/000000726 | DOI Listing |
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