Connect with us

Health

Study shows how cancer can selfishly hijack a helpful immune pathway to spread

Study shows how cancer can selfishly hijack a helpful immune pathway to spread
Study shows how cancer can selfishly hijack a helpful immune pathway to spread

 


A study led by researchers at Memorial Sloan Kettering Cancer Center (MSK) and Weill Cornell Medicine 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. 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.”

Dr. Samuel Bakhoum, researcher and radiation oncologist at MSK, and one of the study’s two senior authors

The findings, which were published Aug. 23 in Nature, 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 said. “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 percent. 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, Dr. Ashley Laughney, 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,” said 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 Dr. Jun Li and senior research technician Mercedes Duran from the Bakhoum Lab; and computational scientist Dr. Melissa Hubisz and Tri-Institutional Computational Biology and Medicine graduate student Ethan Earlie from the Laughney Lab.

When cell division goes haywire

Central to the research is a phenomenon known as chromosomal instability.

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

If the chromosomes are the instruction manual for the body, it’s like having some cells that wind up with a lot of duplicated and/or missing pages, he explains.

“We knew that chromosomal instability is an important driver of cancer’s ability to spread, otherwise known as metastasis,” Dr. Bakhoum said. “What we discovered here is that the immune system plays a central role in this process.”

Cooperation between cancer cells and the immune system is driven by STING

A previous collaboration between researchers at MSK and Weill Cornell Medicine, which was also published in Nature, showed the complex chain of events triggered by chromosomal instability leads to changes in cells that drive cancer metastasis.

“That study was done in partially immune-compromised mice,” Dr. Bakhoum said. “So it was really neither here nor there in terms of understanding the role of the immune system.”

To figure out the immune system’s role, the new study used mouse models of cancer that either had fully functional immune systems or greatly weakened immune systems. It also looked at tumor cells with both high and low levels of chromosomal instability, as well as cells missing the STING1 gene, which makes a protein called STING, that activates an inflammatory response when it detects foreign DNA molecules in the cytoplasm.

“What we found was that the effect was largely dependent on the immune system,” Dr. Bakhoum said. “Basically, there is sinister cooperation between cancer cells with chromosomal instability and immune cells -; and that cooperation is driven by STING.”

The results from mouse models of cancer were then validated in healthy cells and tumor samples from human patients.

For example, the researchers treated a simple type of cell, known as a fibroblast, with a STING agonist -; the foundation for the drugs developed for human patients -; and observed a strong initial immune response.

“But by day five, you have basically no immune response left,” Dr. Bakhoum said. “The cells became desensitized to this pro-inflammatory pathway very quickly -; mirroring the response we saw in the cancer cells. Instead, the cells started to signal stress response pathways that dampened the immune response, thus having the opposite effect.”

Digging into complex cell-to-cell interactions

The scientists used a technique called single-cell sequencing to understand all the different cellular players in and around a tumor (also called the tumor microenvironment). The technique allows for the detailed analysis of all the many types of cells involved -; such as macrophages, T cells, B cells, neutrophils and tumor cells -; and the ligands and receptors they express. Notably, to communicate, cells typically emit ligands that bind to complementary receptors on the surface of target cells, thereby triggering a change in the behavior of the target cell. While most methods predict cell-to-cell interactions based on just the mutual expression of complementary ligand-receptor pairs, the research team focused on whether their interaction actually changes the cell receiving the signal.

“One of our most important findings was that altering the level of chromosomal instability or the activation of STING dramatically changes responses in the environment in and around the tumor,” Dr. Laughney said.

And to understand those impactful interactions between the cancer cells and different immune cells, the researchers developed ContactTracing. By design, the tool exploits the variability of real-world biology without the need for prior knowledge.

The method is based on the simple premise that in a given tumor, there is inherent biological diversity -; not every cancer cell is going to secrete the same binding molecule, or ligand. And not every immune cell is going to express the right receptor for that ligand, Dr. Laughney explained.

So, by comparing cells that are interacting to ones that aren’t, the tool gives scientists a clearer picture of what exactly is changed by the interaction between the two.

“When you look at the effects that elicit a response in the cancer microenvironment, all the ligands on those chromosomally unstable cancer cells were associated with a specific cellular stress response -; one that happens to involve STING,” she said.

And when the same interactions were examined in the context of low chromosomal instability or where STING had been depleted from cancer cells, they trigger a different response -; a strong immune response that attacked the cancer cells.

The new ContactTracing method could also help illuminate other areas of biology and disease where cell-to-cell interactions are critical, Dr. Laughney noted.

Findings suggest therapeutic opportunities

The findings from the study suggest an opportunity to improve treatments for the many patients with advanced cancer driven by chromosomal instability, Dr. Bakhoum said.

“It appears the reason activating STING in these patients isn’t very effective is that most patients’ cells are already desensitized to it due to the persistent activation of the pathway from chromosomal instability,” he said. “Counterintuitively, these patients may actually benefit from STING inhibition.”

Treatment of study mice with STING inhibitors reduced chromosomal instability-driven metastasis in melanoma, breast, and colorectal cancer models.

Additionally, by identifying the subset of patients whose tumors can still mount a strong response to STING activation, doctors could select better candidates for STING agonists, Dr. Bakhoum said.

Source:

Journal reference:

Li, J., et al. (2023). Non-cell-autonomous cancer progression from chromosomal instability. Nature. doi.org/10.1038/s41586-023-06464-z

Sources

1/ https://Google.com/

2/ https://www.news-medical.net/news/20230823/Study-shows-how-cancer-can-selfishly-hijack-a-helpful-immune-pathway-to-spread.aspx

The mention sources can contact us to remove/changing this article

What Are The Main Benefits Of Comparing Car Insurance Quotes Online

LOS ANGELES, CA / ACCESSWIRE / June 24, 2020, / Compare-autoinsurance.Org has launched a new blog post that presents the main benefits of comparing multiple car insurance quotes. For more info and free online quotes, please visit https://compare-autoinsurance.Org/the-advantages-of-comparing-prices-with-car-insurance-quotes-online/ The modern society has numerous technological advantages. One important advantage is the speed at which information is sent and received. With the help of the internet, the shopping habits of many persons have drastically changed. The car insurance industry hasn't remained untouched by these changes. On the internet, drivers can compare insurance prices and find out which sellers have the best offers. View photos The advantages of comparing online car insurance quotes are the following: Online quotes can be obtained from anywhere and at any time. Unlike physical insurance agencies, websites don't have a specific schedule and they are available at any time. Drivers that have busy working schedules, can compare quotes from anywhere and at any time, even at midnight. Multiple choices. Almost all insurance providers, no matter if they are well-known brands or just local insurers, have an online presence. Online quotes will allow policyholders the chance to discover multiple insurance companies and check their prices. Drivers are no longer required to get quotes from just a few known insurance companies. Also, local and regional insurers can provide lower insurance rates for the same services. Accurate insurance estimates. Online quotes can only be accurate if the customers provide accurate and real info about their car models and driving history. Lying about past driving incidents can make the price estimates to be lower, but when dealing with an insurance company lying to them is useless. Usually, insurance companies will do research about a potential customer before granting him coverage. Online quotes can be sorted easily. Although drivers are recommended to not choose a policy just based on its price, drivers can easily sort quotes by insurance price. Using brokerage websites will allow drivers to get quotes from multiple insurers, thus making the comparison faster and easier. For additional info, money-saving tips, and free car insurance quotes, visit https://compare-autoinsurance.Org/ Compare-autoinsurance.Org is an online provider of life, home, health, and auto insurance quotes. This website is unique because it does not simply stick to one kind of insurance provider, but brings the clients the best deals from many different online insurance carriers. In this way, clients have access to offers from multiple carriers all in one place: this website. On this site, customers have access to quotes for insurance plans from various agencies, such as local or nationwide agencies, brand names insurance companies, etc. "Online quotes can easily help drivers obtain better car insurance deals. All they have to do is to complete an online form with accurate and real info, then compare prices", said Russell Rabichev, Marketing Director of Internet Marketing Company. CONTACT: Company Name: Internet Marketing CompanyPerson for contact Name: Gurgu CPhone Number: (818) 359-3898Email: [email protected]: https://compare-autoinsurance.Org/ SOURCE: Compare-autoinsurance.Org View source version on accesswire.Com:https://www.Accesswire.Com/595055/What-Are-The-Main-Benefits-Of-Comparing-Car-Insurance-Quotes-Online View photos

ExBUlletin

to request, modification Contact us at Here or [email protected]