This is another paper that show that, in a mouse model, a local radiation therapy of established tumors activates immune system through DNA sensor STING.
First, the authors found that STING-KO mice or IFN-alphaR1 blockade, but not MyD88KO, TRIF-KO, CRAMP-KO (homolog to LL37) mice and anti-HMGB1 blockade, showed impaired ability to control tumor growth after local tumor irradiation.
In vitro experiments showed that STING or IRF3 deficient BmDCs lacked an ability to cross-prime antigen-specific CD8 T cells. This deficiency was thought to be as a result of STING-KO BmDCs' inability to produce IFN-beta in response to irradiated tumor cells, since it was reversed by addition of exogenous IFN-beta.
Similar results were obtained with mice deficient in cGAS, a DNA sensor molecule upstream of STING pathway.
The authors also showed that radiation-induced tumor control was dependent on presence of CD8 T cells and autocrine IFNalphaR signalling in CD11c+ cells.
Finally, the authors showed that intra-tumoral injections of cGAS activators significantly improved tumor control in wild-type but not in STING-KO mice (for some reason, the authors did not show STING-KO control).
In summary, the authors proposed the model wherein DNA (or DNA containing cellular fragments) released after tumor irradiation are captured by local DCs and cross-presented to CD8 T cells in IFN-alphaR dependent manner leading to T cell priming and tumor growth control.
Here too, the authors were unable to decipher the precise mechanisms for cytosolic uptake of tumor DNA by DCs.