Study Uncovers New Way of Exposing Cancers to Immune System Attack  

A pep talk will do little for a team that can’t leave the locker room. As scientists have discovered more than once, a similar principle applies to cancer immunotherapy.  

For many years, efforts to wield the immune system against cancer focused on the “pep talk” strategy — finding ways to rouse the immune system to attack cancer cells. While this approach had some success, it often produced a relatively short-lived immune response, was difficult to administer, and was prone to serious side effects. The breakthrough came when researchers turned the question around: instead of asking how to stimulate the immune response, they looked at what was holding the response back, and how it could be unleashed. The result was a new class of therapies, immune checkpoint inhibitors, that have revolutionized cancer treatment.  

A recent study led by scientists at Dana-Farber, Gilead Sciences, Inc., and the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, demonstrates anew the value of freeing up, rather than revving up, the immune response. The findings, published in Cancer Discovery point to a new target for drugs that weaponize the immune system against cancer.  

The study involves a conga line of cellular proteins known as the cGAS-STING pathway, which plays a key role in the body’s ability to fight infection. When a virus invades a cell, the cGAS protein sniffs out the foreign genetic material and activates STING, which sends a distress signal to the immune system in the form of interferon, which raises the body’s anti-viral defenses.  

In a variety of cancers, STING is silenced, helping the malignancies escape notice by the immune system. Researchers sought to bring these cancers out of hiding with compounds that activate STING, known as STING agonists. In laboratory and animal studies, the agonists showed great promise, but a major hitch arose: the drugs haven’t worked so far in humans.  

An indirect approach 

A study published last year by Dana-Farber investigators explained part of the reason why: “We showed that direct STING agonists are toxic to T cells,” the very cells needed for an immune system assault on cancer, explains David Barbie, MD, who helped lead the study.  

The findings suggested an alternate approach was needed. A group of inherited syndromes in children provided a first clue.  

The syndromes place young people at heightened risk for autoimmune diseases like lupus, in which the immune system stages an aggressive attack on normal, healthy tissue. Research had shown that in many of these cases, the gene TREX1 is mutated and unable to function. When the gene is shut down in mice, studies found, the animals developed a lupus-like condition.  

This suggested that a healthy, functional TREX1 helps cells stave off an immune system attack. “Some early studies indicated that cancer cells sometimes use TREX1 to prevent excess activation of STING,” says Barbie.  

The new paper, of which Barbie is the senior author, confirms that is precisely cancer cells’ strategy. 

Tracking down TREX 

The researchers treated cancer cells with drugs known as MPS1 inhibitors, which are potent activators of STING. When they sequenced the cells’ RNA to see which genes were active, they identified many interferon-related genes, but also some whose job is to shush signals that invite an immune system attack. Among the most active of these was TREX1.  

The implications are clear. When cancer cells find themselves broadcasting their presence through interferon, they activate TREX1 to silence STING and lower their visibility on the immune system’s radar.  

“Our findings suggest that targeting the TREX1 protein with drug agents is a promising way of sparking an immune attack on certain cancers,” says Barbie. “We’ve shown that TREX1 is an innate immune checkpoint, activated by cancer cells to keep the immune system at bay. The success of drugs targeting other immune checkpoints suggest that inhibiting TREX1 may be an effective new strategy against cancer.”