How a Lowly Immune Cell Helps the Immune System Fight Cancer

“The reasons for immunotherapy failures remain largely unknown,” said co-senior author Mikaël Pittet, professor of medicine at UNIGE and a researcher at the Ludwig Institute for Cancer Research. “Deciphering the immune components involved is key to develop more advanced treatments and make immunotherapies a real therapeutic revolution.”

The lowly neutrophil: Underappreciated and misunderstood

Much of the research on the response to immunotherapy has focused on so-called adaptive immune cells. These cells, which include T cells, are activated by immunotherapy and can learn to recognize and attack cancer cells.

However, neutrophils — the most common cell type in the immune system — have garnered considerably less attention. A type of white blood cell, neutrophils are produced in the bone marrow and circulate in blood and tissues. They are quickly mobilized to release antimicrobial chemicals during infection or injury, yet in the context of cancer they tend to promote tumor growth.

“Neutrophils weren’t considered very interesting because they aren’t adaptive, so they can’t learn to tell a tumor cell from a normal cell, but in fact, it’s been known for a while that having a lot of neutrophils in a tumor is a bad sign,” Klein said.

To understand the role of neutrophils in immune response to cancer, in the new study researchers observed what happened when mice with lung or colorectal cancer were given immunotherapy. In tumors that responded well to treatment, much to the researchers’ surprise, the number of neutrophils increased dramatically.

“This first result was in contradiction to what was known about the role of neutrophils in cancer, pushing us to go further to understand why,” Klein said.

In a collaborative effort that brought together complementary expertise, Pittet’s lab designed a set of experiments to compare the identity of neutrophils in tumors that responded well and those that did not respond well to therapy. Klein’s lab developed tools to further analyze neutrophil and tumor differences in detail at the single-cell level.

An immune cell with multiple identities

The team found that neutrophils are not a single, uniform set of cells. Rather, there are multiple types of neutrophils that can be differentiated from each other based on markers on their surface.

Importantly, the neutrophils in tumors that responded to immunotherapy were distinct from those in tumors that progressed. In a series of experiments, the team showed that the subset of neutrophils in the therapy-sensitive tumors could, in fact, suppress tumor growth.

Notably, when the researchers blocked neutrophils in tumors that responded well to immunotherapy, the benefits of treatment disappeared. These observations suggest that cancer-combating neutrophils, although not directly targeted by immunotherapy, play an important indirect role by activating adaptive immune cells and enhancing their ability to kill tumor cells.

“We discovered that neutrophils are, in fact, much more diverse and complex than previously appreciated and appear to be central to an effective therapeutic response,” Klein said. “This is important because it gives us an indicator of when cancer treatments work, and identifies a major player involved.”

Now, the researchers are interested in exploring how they might harness the power of neutrophils to combat cancer and aid immunotherapy.

"It seems that the fate of pro- or anti-tumor neutrophils is already determined in the bone marrow. Would it then be possible to manipulate them to fight tumors?” Pittet asked.

“We need to think of the immune response as a complex system with all the parts talking to each other,” Klein added. “This particular study suggests that we might push neutrophils toward their effective anti-tumor behavior and toward activating other immune responses that are important for fighting cancer.”

If successful, he said, such research could eventually lead to the development of more effective cancer therapies that target neutrophils.

The researchers are also eager to investigate whether the neutrophil responses they observed occur in humans with cancer, and how neutrophil responses vary across different cancer types.

Authorship, funding, disclosures

Additional authors include Jeremy Gungabeesoon, Marie Siwicki, Peter Koch, Christina Pfirschke, Christopher Garris, and Ralph Weissleder of Mass General and HMS; Nicolas Gort-Freitas of HMS; Michael Mazzola of Mass General; Máté Kiss, Mehdi Hicham, and Florent Duval of University of Geneva and AGORA Cancer Research Center; Evangelia Bolli, Chiara Cianciaruso, and Ruben Bill of HMS, University of Geneva, and AGORA Cancer Research Center; Marius Messemaker of Mass General, HMS, and Netherlands Cancer Institute; Solange Peters of CHUV and University of Lausanne; and Krisztian Homicsko of AGORA Cancer Research Center, Ludwig Institute for Cancer Research, CHUV, and Swiss Cancer Center Leman.

Funding for the research was provided by the National Institutes of Health (R01-CA218579, P01-CA240239), the ISREC Foundation, Landry Cancer Biology Research Fellowships, a Postdoc.Mobility Fellowship Return Grant of the Swiss National Science Foundation (P400PM_183852, P5R5PM_203164), an EMBO Postdoctoral Fellowship, and a Human Frontier Science Program Postdoctoral Fellowship (LT000017/2021-L).

Pittet has served as a consultant for AstraZeneca, Elstar Therapeutics, ImmuneOncia, KSQ Therapeutics, Merck, Siamab Therapeutics, Third Rock Ventures, and Tidal. Weissleder has served as a consultant for Moderna, Lumicell, Seer Biosciences, Earli, and Accure Health. Bill has received a speaker fee from Janssen, and his wife is an employee and shareholder of CSL Behring.

Adapted from a University of Geneva news release.