Researchers find elusive source of most abundant immune cell

August 28, 2018, La Jolla Institute for Allergy and Immunology
The top left cells represent neutrophil progenitors and the right bottom ones are fully differentiated neutrophils. The color of nucleus matches the color on the viSNE map in the middle, where red indicates higher in the hematopoietic hierarchy and yellow indicates lower. Credit: Dr. Yanfang Peipei Zhu, La Jolla Institute for Allergy and Immunology

Neutrophils—short-lived, highly mobile and versatile—outnumber all other immune cells circulating through the blood stream. Yet, despite the cells' abundance, the progenitor cell that only gives rise to neutrophils had eluded all efforts to track it down. Now, researchers at La Jolla Institute for Allergy and Immunology identified a progenitor of neutrophils in the bone marrow of mice and humans and tied it to cancer-promoting activities.

Their study, published in the August 28, 2018, issue of Cell Reports, found that neutrophil progenitors promote and that the frequency of the usually rare cell increases dramatically in the blood of human melanoma patients. The findings could assist in the detection of cancers by serving as an early warning sign and drive new therapeutic and pharmaceutical approaches for the treatment of neutropenia, chronic inflammation and .

"For many years, the cancer immunology field has been really focused on T cells, which led to the development of checkpoint blockade and CAR-T therapies but there's a whole other arm of the immune system that plays a role in tumorigenesis," says Catherine Hedrick, Ph.D., a professor in the Division of Inflammation Biology, who led the current study. "We found that this particular subset of that promotes tumor growth and shows up in high numbers in melanoma patients. If our initial findings hold up across the board, a simple blood test could indicate if you have cancer or not."

Neutrophils are among the first to arrive at the scene when pathogens breach the body's physical barriers. Equipped with powerful anti-microbial tools, they form the initial line of defense against infections by destroying microbes, mopping up debris and sounding the alarm that alerts the rest of the immune system to an infection. Neutrophils also play a critical role in chronic inflammatory diseases, including cancer.

Despite their abundance and importance, researchers had been unable to trace neutrophils' lineage to their origin in the , where multipotent give rise to a series of increasingly specialized progenitor cells that eventually differentiate into their target cell types, including , lymphocytes and neutrophils.

"Over the years, people identified different white blood cell progenitors but the one that was missing was the neutrophil progenitor because we didn't have the tools to pull the populations apart," says postdoctoral researcher and the study's first author, Yanfang Peipei Zhu, Ph.D. "Now, we can study disease where neutrophils execute unique and important functions and investigate further how certain subsets of them promote tumor growth."

The successful search started with high-dimensional mass cytometry, which is also known as cytometry by time-of-flight (CyTOF). Immune cells are characterized by subtle differences in the expression of a multitude of markers. Each combination serves as a unique cellular ID that allows scientists to distinguish between different types of immune cells. CyTOF allowed Zhu to simultaneously analyze 39 surface markers known to pinpoint hematopoietic stem and progenitor cells, transient myeloid precursors, and terminally differentiated myeloid cells, especially granulocytes, the subset of immune cells neutrophils belong to.

The high-dimensional bird's-eye view led to the discovery of a previously unknown progenitor population with neutrophil characteristics. In vivo adoptive transfer approaches confirmed that this progenitor gives rise only to , bringing a decades-long search for a committed neutrophil progenitor to its successful conclusion.

Once the mouse neutrophil progenitor had been identified, Zhu and her colleagues were able to track down an equivalent neutrophil progenitor in healthy human bone marrow. When transferred in mouse cancer models, both the murine and human neutrophil progenitors promoted tumor growth.

"It seems this works through T , possibly suppressing them and turning them off but we still need to look at the mechanism," says Zhu. "It could be one of the factors that have an impact current immunotherapy by making them less efficient."

Surprisingly, when Zhu compared the blood of healthy people and patients recently diagnosed with melanoma, she found elevated levels of circulating neutrophil progenitors. Zhu is now trying to determine whether the same holds true for other cancers as well. "If so, it could be used as a simple biomarker for early cancer discovery," says Zhu.

Explore further: Communication between lung tumors and bones contributes to tumor progression

More information: Yanfang Peipei Zhu, Lindsay Padgett, Huy Q. Dinh, Paola Marchoveccio, Amy Blatchley, Runpei Wu, Erik Ehinger, Cheryl Kim, Zbigniew Mikulski, Gregory Seumois, Ariel Madrigal, Pandurangan Vijayanand, Catherine Hedrick. "Identification of an Early Unipotent Neutrophil Progenitor with Pro-Tumoral Activity in Mouse and Human Bone Marrow." 2018, Cell Reports. DOI: 10.1016/j.celrep.2018.07.097

Related Stories

Communication between lung tumors and bones contributes to tumor progression

November 30, 2017
Massachusetts General Hospital (MGH) investigators have identified a way in which a type of lung cancer co-opts a portion of the immune system to increase tumor progression. In the Dec. 1 issue of Science, the team from the ...

Angel or devil? For cancer, not all neutrophils are created equal

January 22, 2015
New research from the Hebrew University of Jerusalem shows that the most common form of white blood cells, called neutrophils, contain many different subtypes, of which some fight the development of cancer and others promote ...

The immune cells that help tumors instead of destroying them

December 12, 2017
Lung cancer is the leading cause of cancer-associated deaths. One of the most promising ways to treat it is by immunotherapy, a strategy that turns the patient's immune system against the tumor. In the past twenty years, ...

How ancestry shapes our immune cells

June 1, 2017
Virtually the entire population of sub-Saharan Africa, and some 70% of African Americans, carry a gene variant (allele) which results in a trait referred to as Duffy-negative. It has long been known that carriers of this ...

Engineering innate immunity for therapy

April 13, 2018
Immune system defends our body against pathogens and cancerous cells, but excessive immunity can in turn lead to tissue damages and diseases. For example, scratching the surface of the eye ignites an immune response that ...

Recommended for you

Deciphering the link between skin allergies and the gut microbiota

September 25, 2018
A non-pathogenic fungus can expand in the intestines of antibiotic-treated mice and enhance the severity of allergic airways disease, according to a study published September 20 in the open-access journal PLOS Pathogens by ...

Exposure to farmyard bugs reduces immune overreaction found in childhood asthma

September 24, 2018
Treating new born mice with farmyard microbes reduces wheezing and inflammation in the airways, by 'taming' their immune systems.

Organs are not just bystanders, may be active participants in fighting autoimmune disease

September 24, 2018
Organs affected by autoimmune disease could be fighting back by "exhausting" immune cells that cause damage using methods similar to those used by cancer cells to escape detection, according to a study by researchers at the ...

A Trojan Horse delivery for treating a rare, potentially deadly, blood-clotting disorder

September 21, 2018
In proof-of-concept experiments, University of Alabama at Birmingham researchers have highlighted a potential therapy for a rare but potentially deadly blood-clotting disorder, TTP. The researchers deliver this therapeutic ...

Study shows surprise low-level ozone impact on asthma patients

September 21, 2018
A new study led by UNC School of Medicine researchers indicates that ozone has a greater impact on asthma patients than previously thought. The study, published in the Journal of Allergy and Clinical Immunology, recruited ...

Cancer immunotherapy might benefit from previously overlooked immune players

September 20, 2018
Cancer immunotherapy—efforts to boost a patient's own immune system, allowing it to better fight cancer cells on its own—has shown great promise for some previously intractable cancers. Yet immunotherapy doesn't work ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.