Sensing tumor with a STING

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.

David Usharauli