Tag: immunotherapy

Categories : Cancer Immune SystemTags :

Study Reveals Natural Killer Cells’ Fuel Source

On By ModernMedia
Pictured is a false-colour scanning electron micrograph of an oral squamous cancer cell (white) being attacked by two cytotoxic T cells (red), part of a natural immune response. Photo by National Cancer Institute on Unsplash

Scientists have discovered how natural killer (NK) cells fuel their activities when fighting infections, which will in turn help inform the development of immune therapies.

When it comes to dealing with infections and cancer, if T cells are like a team of specialist doctors in an emergency room, then NK cells are the paramedics: They arrive first on the scene and perform damage control until reinforcements arrive. Their existence was revealed in the 1970s when scientists were trying to characterise T cell cytotoxicity.

NK cells belong to our innate immune system, which dispatches these first responders, and they come with a built-in ability to recognise and respond to danger. Learning what powers NK cells is an ongoing area of immunology research, with important clinical implications.

“There’s a lot of interest right now in NK cells as a potential target of immunotherapy,” said Joseph Sun, an immunologist in the Sloan Kettering Institute. “The more we can understand what drives these cells, the better we can program them to fight disease.”

First responders

Previous studies have shown that aerobic glycolysis provides the energy for T cells to carry out their protective activities. But it was not known whether NK cells use this form of metabolism in performing their functions.

Dr Sun and his colleagues studied NK cells in animal models instead of in vitro, in order to find out, in a natural setting, what type of metabolism NK cells use and compare it to T cells. They discovered that NK cells increase aerobic glycolysis about five days before T cells respond with their own glycolytic surge.

“This fits with the idea that NK cells are innate immune cells that are really critical for mounting a rapid response,” said Research Fellow Sam Sheppard.

The findings are relevant to ongoing efforts to use NK cells as immunotherapy in people with cancer and other conditions. These are particularly relevant for procedures that make use of NK cells as a form of cell therapy—when cells are grown outside the body and then introduced back into the patient.

Finding a delicate balance

“If you’re growing these cells in a dish and you push them to divide too rapidly, they may not have as much potential to undergo aerobic glycolysis when you put them into a patient,” Dr Sheppard explained.

For researchers designing clinical trials, the goal is to find a balance between encouraging NK cells to multiply and preserving their stamina. These NK cells are the paramedics of our immune system, so it’s important to keep them speedy and responsive.

The findings were reported June 1, 2021, in the journal Cell Reports.

Source: Eureka Alert

Categories : CancerTags :

Study Discovers How Melanoma Cells Hide From Immune System

On By ModernMedia

Melanomas in some patients do not respond well to immunotherapy treatments, and now researchers have discovered that a defect in STING gene expression in melanoma cells helps them escape immune cell surveillance.

Cancer cells use a variety of recently discovered mechanisms to avoid detection and destruction by immune cells, including defective detection and destruction of T cells, losses in expression of critical proteins on tumour cells and defective cell signaling in both immune and tumor cells.

The interferon signaling pathway is an important signaling pathway in interactions between tumour and immune cells. This pathway increases expression of molecules allowing tumour cells to be targeted by immune cells. One of the interferon signaling pathway’s key molecules is STING, which is activated by the protein cGAS.

Previously Moffitt researchers showed that STING activity is suppressed and altered in a subset of melanomas, rendering tumour cells invisible to the immune system.

Using a process called epigenetic modification to turn genes on or off with methylation groups, the researchers sought to improve the understanding of alterations in STING signaling in melanoma and find out how STING expression is suppressed. 

The researchers performed a series of laboratory experiments and discovered that the DNA regulatory region of the STING gene is highly modified by methylation groups resulting in loss of STING gene expression in certain melanoma cell lines. Importantly, they confirmed these findings in patient clinical samples of early and late-stage melanomas and showed similar methylation events and loss of expression of the upstream STING regulator cGAS.

The researchers demonstrated the possibility of reactivating STING and/or cGAS expression with a demethylating drug or genetic approaches. These successfully reactivated STING activity, resulting in increased interferon levels when triggered by STING agonist drugs that enabled the melanoma cells to now be recognised and targeted by immune cells.

“These studies show the critical importance of an intact STING pathway in melanomas for optimal T cell immunotherapy success, and how to overcome a notable STING defect in melanoma cases of gene hypermethylation by a combination therapy,” said senior author James J. Mulé, PhD, and Associate Center Director, Translational Science, H. Lee Moffitt Cancer Center & Research Institute.”Unless patients’ melanomas are pre-screened for intact versus defective STING, it is not at all surprising that clinical trials of STING agonists have, to date, uniformly failed.”

Source: News-Medical.Net

Journal information: Falahat, R., et al. (2021) Epigenetic reprogramming of tumor cell–intrinsic STING function sculpts antigenicity and T cell recognition of melanoma. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2013598118.