New research shows how cancer rewires a key immune pathway to spreadDate: August 23, 2023
Source: Memorial Sloan Kettering Cancer Center
Summary: A study has discovered a new relationship between cancer cells and the immune system, and shows how cancer can selfishly hijack a normally helpful immune pathway.
Usually, activation of this key immune pathway -- called the STING pathway -- triggers a strong inflammatory response that protects the body from foreign and unhealthy cells. But prolonged activation of the same pathway leads to a desensitization and ultimately to a "rewiring" of cellular signaling, which aids and abets cancer's spread, the researchers found.
"You might think of it like a car alarm," says Samuel Bakhoum, MD, PhD, a researcher and radiation oncologist at MSK, and one of the study's two senior authors. "If it goes off rarely, that's going to get your attention. But if it's going off all the time, you're going to get used to it and tune it out."
The findings, which were published in Nature on August. 23, help explain why drugs to activate STING (known as STING agonists) have been unsuccessful in clinical trials in patients with advanced cancer, and suggest, counterintuitively, that many patients may actually benefit from drugs that block STING activation (STING inhibitors).
"There's been millions of dollars invested in drugs that activate the STING pathway to fight cancer, and so far in clinical trials, they have not shown significant anti-cancer efficacy," Dr. Bakhoum says. "In the lab, these drugs held a lot of promise -- but in one trial of 47 patients, there were only two whose cancers even showed a partial response. In another trial of more than 100 patients that combined STING agonists with another immunotherapy, the overall response rate was 10%. So the question driving this research was, 'Why don't they work despite such promise in the preclinical setting?'"
The team's discoveries were made possible through the development of an innovative computational tool in the lab of the study's other senior author, Ashley Laughney, PhD, an assistant professor of physiology and biophysics and member of the Institute for Computational Biomedicine at Weill Cornell Medicine. Dubbed ContactTracing, the approach predicts cell-to-cell interactions and also examines how different cells respond to stimuli in growing tumors. By mapping interactions into a mandala-like pattern, the tool revealed that the long-term activation of the STING pathway leads to changes in cellular signaling that attracts cells that suppress the immune response to the area in and around the tumor.
"This isn't just another tool to document whether cell type A might interact with cell type B," says Dr. Laughney, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. "We're looking at whether and how these interactions actually affect the cell receiving the signal."
The study was led by a team of four co-first authors from the Bakhoum and Laughney laboratories: postdoctoral fellow Jun Li, PhD, and senior research technician Mercedes Duran, MS, from the Bakhoum Lab; and computational scientist Melissa Hubisz, PhD, and Tri-Institutional Computational Biology and Medicine graduate student Ethan Earlie, MS, from the Laughney Lab.
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Source:
https://www.sciencedaily.com/releases/2023/08/230823122523.htm
