A team led by Weill Cornell Medicine scientists has shown a surprising discovery that white blood cells called neutrophils play an immeasurable role in eradicating solid tumors.
In the study published March 30 in the cellIn this study, researchers investigated how T-cell-based immunotherapy can destroy melanoma tumors even though many cancer cells lack the markers, or “antigens,” that T cells target. They found that, by attacking tumors, T cells activate a swarm of neutrophils – which in turn kill cancer cells that T cells cannot eliminate. The findings could lead to new immunotherapies that harness this unexpected but potent immune response against tumors.
“We’ve tended to think of innate cells as immune cells that can, at best, help trigger a tumor’s primary T-cell response. In addition, several studies have shown that neutrophils support tumor development, but here we reveal that they can have Study co-author Dr. Taha Marghoub, MD, deputy director of the Sandra and Edward Meyer Cancer Center and the Margaret and Hermann Sokol Professor of Oncology, said a critical role in tumor suppression and elimination would elude T-cell therapy. Cornell, and co-director of the Ludwig Collaborative Laboratory.
“This work clearly shows us that the term homozygous ‘neutrophil’ needs to be more specific, based on the use of single-cell technology,” said co-senior author Dr. Jedd Wolchok, MD, director of the Meyer Cancer Center. Professor of Medicine at Weill Cornell Medicine, co-director of the Ludwig Collaborative Laboratory and an oncologist at New York-Presbyterian/Weill Cornell Medical Center. “In the past, this generic term referred to a group of cells that were not thought to be useful in controlling tumors. We now know that a subset of these cells are important in improving engineered T-cell therapies to overcome heterogeneity.”
Cancer immunotherapies, which harness or enhance the ability of immune cells to attack malignant cells, have begun to revolutionize cancer treatment over the past decade. In some cases, these therapies have essentially cured advanced cancer patients who had no hope of survival. However, for most types of cancer, immunotherapies are only effective in a minority of patients. Overall, researchers still have a lot to learn about how anti-cancer immunotherapies work and how their effectiveness can be improved.
In this study, the researchers studied an experimental immunotherapy that includes a drug to boost T-cell activity and proliferation, as well as T cells engineered to recognize an antigen associated with skin cancer. Tumors can sometimes evade immunotherapy that targets a specific tumor antigen simply by stopping expressing that antigen—cancer cells that do not express the antigen are called “escape variants.” However, the researchers found that their T-cell-boosting therapy could eradicate melanomas, in standard mouse models, even when a large portion of the melanoma cells lacked their target antigen, Trp1.
Ultimately, they determined that the primary antitumor activity of T cells against Trp1-expressing melanoma cells led to a secondary tumor-killing response – from neutrophils. These white blood cells are known to be the first responders to infections and wounds. As members of the evolutionarily older “innate” immune system, they don’t target specific antigens the way T cells do. However, the authors concluded that neutrophils that were invoked by T-cell immunotherapy were indeed responsible for killing the remaining melanoma cells that did not express Trp1—at least in part by secreting the highly reactive molecule nitric oxide.
As part of the study, the researchers identified a distinct gene expression pattern in tumor-fighting neutrophils, and found that in a widely used database of melanoma patients, the greater occurrence of this gene expression “signature” in tumor samples from biopsy was associated with better survival. results for patients.
The results were particularly surprising because previous studies had shown that neutrophils around a tumor often act as they do allies From the tumor – the tumor is involved in helping it survive and spread, which it does in part by suppressing other elements of anti-tumor immunity.
In any case, the new findings suggest that, in the context of robust immunotherapy involving engineered T cells targeting tumor antigens, and a general enhancement of T-cell functions, neutrophils could play an important role in resistance to tumors—in fact, an essential component. A role in clearing the altered cancer cells that would keep the tumor alive.
“Traditional T-cell-based therapies have been successful in treating cancers, but they are not effective against heterogeneous tumours, which contain antigen-escape variants that can be invisible to the immune system,” said Dr. Daniel Hirschhorn, assistant professor of research. in pharmacology at Weill Cornell Medicine. “It was incredibly surprising to discover that T-cell-educated neutrophils can eliminate these ‘invisible’ cancer cells. This discovery highlights the importance of mobilizing multiple arms of the immune system in the fight against cancer.”
Researchers are now continuing to study these anti-tumor neutrophils, to determine how best to stimulate and target them — as cancer fighters on their own, or as boosters for other immune therapies.
“I also hope that we can find a way to use measures of these anti-tumor neutrophils in tumor biopsies as biomarkers that help us choose the best treatments for patients,” said Dr. Marghoub.