The results of study show that repeated stimulation of same pathway induces desensitization and, eventually, a “rewiring” of cellular signaling that favors the growth of cancer.

A study by MSK and Weill Cornell Medicine reveals a new interaction between cancer cells and the immune system, revealing how cancer can hijack the beneficial STING pathway, a crucial immunological route that often results in a potent inflammatory response to defend against foreign and harmful cells.

The results of the study show that repeated stimulation of the same pathway induces desensitization and, eventually, a “rewiring” of cellular signaling that favors the growth of cancer.

One of the two senior authors of the study and a radiation oncologist at MSK, Dr. Samuel Bakhoum, said that it may be compared to a vehicle alarm. “If it just sometimes goes off, that will catch your attention. However, if it constantly beeps, you’ll become used to it and tune it out.

The research, which was reported in Nature, provides an explanation for why STING agonists—drugs that work to activate STING—have not been successful in clinical trials in patients with advanced cancer. It also suggests—contrary to popular belief—that many patients might actually benefit from STING inhibitors.

Dr. Bakhoum stated, “Millions of dollars have been spent on drugs that activate the STING pathway to fight cancer, but so far in clinical trials, they have not demonstrated any appreciable anti-cancer efficacy.” “These medications showed great promise in the lab, but in one trial of 47 patients, just two individuals’ tumors even displayed a partial response.

The overall response rate was 10% in a different study with more than 100 patients that paired STING agonists with another treatment. Therefore, the research’s main issue was “Why don’t they work despite showing such promise in the preclinical setting? “.

The study’s other senior author, Dr. Ashley Laughney, an assistant professor of physiology and biophysics and a member of the Institute for Computational Biomedicine at Weill Cornell Medicine, developed a novel computational tool that enabled the team’s findings.

The method, known as “ContactTracing,” looks at how various cells react to stimuli in developing tumors and predicts cell-to-cell connections. The tool demonstrated that long-term stimulation of the STING pathway results in alterations in cellular signaling that draw cells that inhibit the immune response to the region inside and surrounding the tumor.

“This isn’t just another tool to document whether cell type A might interact with cell type B,” said Dr. Laughney, who is also a part of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. We are investigating if and how these interactions influence the cell that is receiving the signal. Chromosomal instability, a phenomena, is at the heart of the investigation.

“It’s a feature of cancer, especially advanced cancers, where the normal process of cell division goes haywire,” said Dr. Bakhoum, whose lab is a member of the Human Oncology and Pathogenesis Program at MSK.

He says that if the chromosomes represent the body’s instruction manual, having some cells result in many duplicated and/or missing pages. Dr. Bakhoum stated, “We knew that chromosomal instability is an important driver of cancer metastasis, or the ability to spread.”

“What we found here is that the immune system plays a key role in this process,” the researcher said. STING promotes interaction between cancer cells and the immune system Researchers from MSK and Weill Cornell Medicine previously worked together, and their findings, which were also published in Nature, demonstrated how chromosomal instability sets off a complicated series of events that alter cells and promote cancer spread. According to Dr. Bakhoum, “that study was conducted in partially immune-compromised mice.”

According to research, the immune system plays a significant role in the development of cancer. Researchers employed tumor cells with high or low levels of chromosomal instability, as well as mice models of cancer with immune systems that were either completely functioning or compromised.

Additionally, they looked at cells lacking the STING1 gene, which makes the STING protein, which triggers an inflammatory response when it identifies foreign DNA molecules. According to the findings, STING is the catalyst for this collaboration between cancer cells and immune cells.

In healthy cells and tumor samples from human patients, researchers have verified their findings from mice models of cancer. They discovered that fibroblast cells initially displayed a strong immunological response when they were treated with a STING agonist.

On day 5, however, the cells lost their sensitivity to the pro-inflammatory pathway, which reduced the immunological response. They had the opposite impact, signaling stress response pathways that slowed the immunological response.

Single-cell sequencing was used by researchers to examine the macrophages, T cells, B cells, neutrophils, and tumor cells that make up the tumor microenvironment. The method made it possible to analyze cell types, ligands, and receptors in great detail.

Normally, cells release ligands that attach to receptors on target cells and cause those cells to behave differently. Instead of relying just on the reciprocal expression of ligand-receptor pairings, the study team sought to ascertain if these interactions truly alter the cell that is receiving the signal.

Researchers have developed a tool called ContactTracing to understand the interactions between cancer cells and immune cells. The tool exploits the variability of real-world biology without the need for prior knowledge.

It is based on the premise that in a given tumor, there is inherent biological diversity, as not every cancer cell secretes the same binding molecule or the right receptor for that ligand. By comparing cells that are interacting to those that aren’t, the tool provides a clearer picture of what is changed by the interaction between the two.

According to a research, ligands on cancer cells with unstable chromosomes cause a particular cellular stress response that involves STING. These interactions result in a potent immune response that kills cancer cells when low chromosomal instability or STING pathways is diminished.

The ContactTracing approach may aid in the comprehension of different biological processes and medical conditions where cell-to-cell interactions are crucial. The results point to a chance to enhance therapies for cancer patients who have advanced disease brought on by chromosomal instability.

It is ineffective to activate STING in certain individuals because their cells have become sensitive to it as a result of chromosomal instability.

However, therapy with STING inhibitors decreased chromosomal instability-driven metastasis in melanoma, breast, and colorectal cancer models, suggesting that these individuals could gain from STING inhibition. Selecting patients with robust tumor responses might facilitate the selection of STING agonist candidates.