New Study Explains Why Some Tumors Do Not Respond to Immunotherapy

Sometimes bits of DNA from unstable chromosomes end up where they don't belong: outside of a cell's central nucleus and floating in the cytoplasm. Cells interpret these rogue bits of DNA as evidence of viral invaders, which sets off their internal alarm bells and leads to inflammation. Immune cells travel to the site of the tumor and churn out defensive chemicals. A mystery has been why this immune reaction, triggered by the cancer cells, does not spell their downfall.

"The elephant in the room is that we didn't really understand how cancer cells were able to survive and thrive in this inflammatory environment," says Samuel Bakhoum from Memorial Sloan Kettering, senior author of a paper published yesterday in Cancer Discovery.  As explained in the paper, the reason has to do, in part, with a molecule sitting on the outside of the cancer cells that destroys the warning signals before they ever reach neighboring immune cells.

Previous work on warning signals from the Bakhoum lab had shown that cGAS-STING signaling inside of cancer cells causes them to adopt features of immune cells—in particular, the capacity to crawl and migrate—which aids their ability to metastasize. This provided part of the answer to the question of how cancer cells survive inflammation and aid metastasis in the process. The new research shows how the cancer cells cope with the warning signals that activated cGAS-STING releases into the environment. A scissor-like protein shreds the signals, providing a second way the cells can thwart the threat of immune destruction.

The scissor-like protein that coats cancer cells is called ENPP1. When cGAMP finds its way outside the cell, ENPP1 chops it up and prevents the signal from reaching immune cells. At the same time, this chopping releases an immune-suppressing molecule called adenosine, which also quells inflammation.

Through a battery of experiments conducted in mouse models of breast, lung, and colorectal cancers, the team showed that ENPP1 acts like a control switch for immune suppression and metastasis. Turning it on suppresses immune responses and increases metastasis; turning it off enables immune responses and reduces metastasis.

From a treatment perspective, perhaps the most notable finding of the study is that flipping the ENPP1 switch off could increase the sensitivity of several different cancer types to immunotherapy drugs called checkpoint inhibitors. The researchers showed that this approach was effective in mouse models of cancer.