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Of Mice Not Men: Immune cells as potential targets for cancer therapy

This is a recurring column on early stage research in animals or other laboratory models that has not entered the clinic yet but could have implications for future research and development of human medicines.

Immune cells as potential targets in breast cancer treatment

Researchers at the University of Pennsylvania School of Veterinary Medicine may have found a way to disrupt the microenvironment of triple-negative breast cancer.

Triple-negative breast cancer, or TNBC, is one of the most aggressive and deadly types of breast cancer. This subtype has a high incidence of tumor relapse and metastases and can be resistant to chemotherapy.

TNBCs do not have receptors for estrogen, progesterone and human epidermal growth factor receptor 2, or Her2, which fuel the growth of the disease. Thus TNBCs do not respond to hormone therapy, such as tamoxifen and Pfizer Inc.'s Aromasin, or treatment aimed at Her2 receptors, such as Roche Holding AG's blockbuster cancer drug Herceptin.

TNBC patients, compared to non-TNBC ones, have higher bloodstream levels of immune cells called myeloid-derived immunosuppressor cells, or MDSCs, a condition associated with poor survival. However, the role these cells play in disease progression and the mechanism through which they promote disease were initially unclear.

"How are the immune cells helping cancer cells?" asked Rumela Chakrabarti, an assistant professor of biomedical sciences and one of the study's lead investigators. "It seems they are helping cancer stem cells grow faster."

Using mouse models and tissue transplants, Chakrabarti and her colleagues found that a protein called deltaNp63 directed MDSCs to tumors and metastatic sites, fueling the growth and spread of tumors.

By altering levels of deltaNp63, the researchers were able to affect the cancer's behavior. They reduced tumor growth and metastasis in mouse models by blocking either deltaNp63 or MDSCs. By lowering levels of deltaNp63, they were able to decrease tumors' aggressiveness and reduce levels of MDSCs going to the tumors without affecting other types of immune cells.

"We're excited because we think our findings could make a big difference for triple-negative breast cancer patients," said Chakrabarti. "Not only can deltaNp63 be used as a biomarker to help personalize treatment regimens, but targeting it may also provide an additive treatment for triple-negative breast cancer, in addition to chemotherapy and radiation," she added.

The study was published in the Journal of Clinical Investigation.

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Neutrophils and lung cancer

In another study on the relationship between immune cells and a tumor's microenvironment, researchers examined the role of neutrophils in lung cancer.

Neutrophils are immune cells that are the first cell types to respond to a trauma, helping the body fight infection.

A study led by Trudy Oliver, cancer researcher and associate professor of oncological sciences at the Huntsman Cancer Institute at the University of Utah, used a mouse model and single-cell sequencing technology to look at interactions between neutrophils and different types of lung cancer.

Results from the study, published in the journal Immunity, showed that tumors altered neutrophil behavior, causing these immune cells to deviate from their normal roles and help the tumors grow.

High levels of neutrophils have previously been associated with poor prognosis in lung cancer and poor response to immunotherapies.

"The association of high presence of neutrophils with a bad response to immunotherapy means neutrophils might be a target for scientists to develop new treatments to help people who aren't responding well to currently available drugs," Oliver said.

The researchers plan to follow up on the study to evaluate whether manipulating neutrophils can help patients respond to lung cancer therapies.

Sleep loss and accelerated Alzheimer's disease pathology in young mice

Mice with chronic disrupted sleep experienced an accelerated display of symptoms related to Alzheimer's disease, according to a study published in the journal JNeurosci.

In a study on male and female mice, researchers led by Sigrid Veasey, a professor at the Center for Sleep and Circadian Neurobiology at the University of Pennsylvania's Perelman School of Medicine, looked at two types of sleep disruption: chronic short sleep and chronic fragmentation of sleep.

Both types were associated with the earlier onset of motor impairment, a major cause of physical disability in adolescent and young adult mice. Further, sleep disruption caused an increase in the pathology of tau protein in two parts of the brain — the amygdala and the locus coeruleus, the brain region that shows the earliest degeneration in Alzheimer's.

According to the study, the progression of neurodegenerative diseases may be warded off with healthy sleep habits in young adults.