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Tumors stressed by cancer immunotherapy release their mitochondrial DNA into the closer immune cells, causing a host alert system. The chemical alert through the molecule cGAS is an important immune-system sensor for DNA that is in the interior of cells, the cytosol, where DNA should not exist.
cGAS connected the innate immune system, which senses initial threats; and the adaptive immune system, which amplifies the anti-tumor response after getting the alert from the innate immune system. The adaptive system battles recurring threats from pathogens. Checkpoints are molecular barriers that cancer cells produce to make themselves undetectable to the immune system. The plan of immunotherapy is to make the cancers detectable.
Current immune checkpoint blockade therapy has been life-extending for many people. The drug targets CD47, a cell surface protein highly expressed in some tumor cells. CD47 signal to block immune cells from killing the cancer cells. cGAS as an innate immune sensor of DNA led to speculation that inhibition of cytosolic DNA sensing could represent a strategy tumor cells used to evade the immune system.
CD47 is found in every cell of the body, and it has long been known that many kinds of cancer cells produce higher amounts of CD47 than healthy cells. CD47 signal helps cancer cells evade detection from the immune system’s killer T-cells.
The higher the levels of CD47 found in tumors, the poorer the prognosis for many cancers. Using mouse cells,
the researchers discovered that when cancer cells are stressed by an experimental anti-CD47 immunotherapy, it leaks DNA into nearby dendritic cells, which present antigens to killer T-cells and are considered a bridge between the innate and adaptive immune systems.
The DNA sensor cGAS sounds the alarm inside those dendritic cells, setting off a signaling cascade that alerts the
immune system and unleashes the cancer-killing T-cells. cGAS is essential for cancer immunotherapy by immune checkpoint blockade. Activating DNA comes from the mitochondria of the cancer cells. Tumor-originated mtDNA was recognized by the DNA sensor cGAS in dendritic cells during anti-CD47 treatment.
cGAS-STING-IRF3 signaling pathway plays a critical role to drive robust innate and adaptive immune response upon anti-CD47 therapy. Understanding this mechanism of anti-CD47 therapy may make it possible to design new combination strategies to improve current immune checkpoint blockade therapies by modulating the innate sensing of mtDNA.