Newly Discovered Protein Complex Pathway Found to Be Key to Radiation-Induced Antitumor Immunity

A recently discovered protein complex called STimulator of INterferon Genes (STING) plays a key role in detecting the presence of tumor cells and triggers an aggressive antitumor response by the body’s innate immune system.

The two separate studies, published November 20, 2014, in the journal Immunity, both conducted by investigators from the University of Chicago (IL, USA) have key implications for the increasing field of cancer immunotherapy. The findings show that when activated, the STING pathway triggers a natural immune response against the tumor. This includes the generation of chemical signals that help the immune system identify tumor cells and generate specific killer T cells. Moreover, the researchers revealed that targeted high-dose radiation therapy triggers the activation of this pathway, which then stimulates immune-mediated tumor control.

These findings could “enlarge the fraction of patients who respond to immunotherapy with prolonged control of the tumor,” according to a commentary on the studies by the University of Verona’s (Italy) Vincenzo Bronte, MD. “Enhancing the immunogenicity of their cancers might expand the lymphocyte repertoire that is then unleashed by interference with checkpoint blockade pathways,” such as anti-PD-1.

STING is a vital part of the process the immune system relies on to identify threats—such as infections or cancer cells—that are noticeable by the presence of DNA that is damaged or in the wrong place, inside the cell but outside the nucleus. Detection of such “cytosolic” DNA initiates a range of interactions that lead to the STING pathway. Activating the pathway triggers the production of interferon-beta, which in turn warns the immune system to the threat, helps the system detect cancerous or infected cells, and ultimately sends activated T cells into the battle.

“We have learned a great deal recently about what we call checkpoints, the stumbling blocks that prevent the immune system from ultimately destroying cancers,” said Thomas Gajewski, MD, PhD, professor of medicine and pathology at the University of Chicago, and senior author of one of the studies. “Blockade of immune checkpoints, such as with anti-PD-1, is therapeutic in a subset of patients, but many individuals still don’t respond. Understanding the role of the STING pathway provides insights into how we can ‘wake up’ the immune response against tumors. This can be further boosted by checkpoint therapies.”

The two published studies, Dr. Gajewski noted, help push this application forward. In a series of research experiments in mice, both groups found tumor cell-derived DNA could trigger an immune response against tumors. However, when tested in mice that lacked a functional gene for STING, the immune system did not effectively respond. “Innate immune sensing via the host STING pathway is critical for tumor control by checkpoint blockade,” the authors stated in their article. They found potential drugs known as checkpoint inhibitors—such as anti PD-1 or anti PD-L1, which can block an immune response—were not effective in STING-deficient mice. New agents that stimulate the STING pathway are being developed as potential cancer therapeutics.

A second University of Chicago team, led by cancer biologist Yang-Xin Fu, MD, PhD, professor of pathology, and Ralph Weichselbaum, MD, chairman of radiation and cellular oncology and co-director of the Ludwig Center for Metastasis Research, demonstrated that high-dose radiation therapy not only kills targeted cancer cells but the resulting DNA damage fuels a systemic immune response. “This result unifies traditional studies of DNA damage with newly identified DNA sensing of immune responses,” Dr. Fu said. “This is a previously unknown mechanism,” Dr. Weichselbaum added.

In mice that lacked STING, however, there was no therapeutic immune response. The induction of interferons by radiation and consequent cancer cell killing, they conclude, depends on STING-pathway signaling. They did find that combining cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), an earlier step in the STING pathway, with radiation, could greatly enhance the antitumor effectiveness of radiation.

“This opens a new avenue to develop STING-related agonists for patients with radiation-resistant cancers,” Dr. Fu concluded.

Related Links:
University of Chicago