Activated neutrophils can be potent anticancer agents

Elevated levels of immune cells called neutrophils in tumors are associated with poor prognosis in cancer patients. However, a study led by researchers at the Stanford University School of Medicine found that direct injection into tumor sites in mice could turn these cells from black sheep into a potent anti-cancer drug.

This treatment eliminated pre-existing tumors and reduced the number and size of subsequent metastases in mice with skin, lung, breast, and colon cancers. They also activated human neutrophils to kill human cancer cells in dishes, suggesting that this approach could be useful in treating patients with many types of cancer.

The researchers infused tumors with three drugs simultaneously: one that summons neutrophils to the tumor, one that enhances the neutrophils’ ability to kill cells, and another that helps find and trap cancer cells. bottom. In an early study, he was eliminated after two treatments, two days apart. melanoma Tumors disappeared in 7 of 8 mice, and the mice remained cancer-free until the end of the study after 5 months. In contrast, untreated animals experienced uncontrolled tumor growth and were euthanized within 1 month.

These are amazing discoveries. Clearly, mice are not people, but it is very rare for existing tumors to be completely eradicated. We are working towards “

Edgar Engleman, MD, Professor of Pathology and Medicine, Stanford University School of Medicine

Engleman is the senior author of a study published online January 26. cancer cellPostdoctoral researcher Dr. Ian Linde is the lead author of the study.

(almost) symbiotic relationship

Researchers in Engleman’s lab have been working for decades to understand how the immune system responds to cancer. It’s a subtle push and pull, they found.

“Cancer and the immune system have a close, almost symbiotic relationship,” Engleman said.

The immune system can be a powerful destroyer of cancer cells, but many cancers have found sneaky ways to exploit that safety valve, preventing the erroneous destruction of healthy cells and autoimmune diseases. It may disguise itself as a healthy cell, secrete substances that tell the immune system to stop rather than attack, or harbor molecules on its surface. It focuses on unlocking the power of the immune system by disabling signals.

Neutrophils are part of what is known as the innate immune system and recognize broad categories of common threats, but are unable to identify and attack specific intruders. , antibodies launched by B cells or specialized receptors on the cell surface T cells Neutrophils are finely tuned to recognize unique protein structures called antigens of pathogens. You can also maintain a delicate balance between

“We still don’t know why neutrophils can have different, seemingly contradictory functions,” Engleman said. “They effectively kill cells infected with bacteria and viruses. But they can also suppress the immune response, and when they infiltrate tumors, they almost always have bad consequences.”

Surprise discovery

Linde injected tumors in lab mice with different combinations of molecules called cytokines. This his Engleman lab had previously shown to modulate the immune response to cancer.

“We didn’t set out to study neutrophils per se,” said Engleman. “But Ian came to me and said, ‘The neutrophils are infiltrating the tumor and the tumor cells are dying.’ We really didn’t expect that. But , he repeated the experiment, and seeing how strong and reproducible the results were, I became more and more enthusiastic.”

Linde describes a cytokine called tumor necrosis factor that attracts neutrophils to tumors, an antibody called CD40 that activates the killing ability of neutrophils, and another antibody that binds to the surface of tumor cells in mice with several types of cancer. I tested a combination of Of the treated animals, 7 out of 10 had melanoma, 8 out of 10 had breast cancer, 8 out of 10 had colon cancer, and 4 out of 10 had lung cancer. Tumor disappeared and survived for at least 60 days without a detectable tumor. In contrast, mice pretreated with antibodies that eliminate neutrophils did not survive to the end of the experiment, indicating that the cancer-killing activity is due to the presence of neutrophils. .

Linde then tested the ability of this treatment, which researchers dubbed neutrophil activation therapy, to prevent cancer cells from migrating to other parts of the body. He found that injecting activating therapy into primary melanoma tumors inhibited the ability of other melanoma cells to colonize and proliferate in the animal’s lungs, a common site for melanoma metastasis.

“Our theory is that neutrophils kill infused tumors, and dead cancer cells and their antigens enter the lymph nodes and activate T cells to seek out and kill distant metastases,” Engleman said. rice field.

Further studies have shown that neutrophils kill tumor cells by stimulating the production of molecules called reactive oxygen species. This molecule can damage DNA and proteins and cause cell death.

Further research is needed to test neutrophil activation therapy in cancer patients. However, Linde showed that human neutrophils exposed to her three components of the combination therapy were stimulated to kill human cancer cells in laboratory dishes.

“This suggests that activated neutrophils could potentially be used as a cell therapy,” said Engleman. “We were able to take the patient’s neutrophils and activate them in the lab before returning them to the patient. Using it can be very effective.

Engleman hopes to begin human clinical trials soon.

“Our results run counter to current belief that neutrophils are tumor-promoting,” Engleman said. “But this is not a shock, because in some cases neutrophils can be very effective killer cells.”

Researchers at the University of Pennsylvania also contributed to this work.

Engleman and Linde filed a patent based on their research.