Tumor-triggered neutrophils can shut down cancer-killing T cells

Certain white blood cells in the immune system, known as neutrophils, can make cancer immunotherapy less effective, according to a new study from Karolinska Institutet published in the journal Immunity. The results show that a signaling molecule in the tumor affects neutrophils, reducing the effect of treatment.

Immunotherapy is used to activate the body’s own immune system against cancer, but not all patients respond to the treatment. In the new study, researchers investigated how neutrophils influence different forms of immunotherapy in two mouse models of melanoma and breast cancer. Neutrophils play an important role in fighting infections, but can have different functions in tumors.

The researchers compared mice with normal neutrophil levels with mice that completely lacked these cells. When neutrophils were absent, several immunotherapies were more effective. Tumors shrank more, and higher numbers of T cells, immune cells that can kill cancer cells, entered the tumor and became activated.

“We see that neutrophils can dampen the effect of immunotherapy by influencing T-cell activity,” says Shengduo Pei, former doctoral student at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, and the study’s first author.

Tumor signals influence treatment

The study also shows that neutrophils themselves change in response to treatment. When immunotherapy is initiated, neutrophils begin to express PD-L1, a protein that inhibits T-cell activity. This change is driven by the signaling molecule interferon-gamma, produced by activated immune cells within the tumor. When the researchers specifically removed PD-L1 or the interferon-gamma receptor from neutrophils, the treatment became more effective.

“This means that the neutrophil response to immunotherapy is not static but governed by signals in the tumor environment. It also shows the importance of studying blocking mechanisms that arise once treatment begins. The results may contribute to the development of treatments that combine several therapies to counteract these inhibitory effects,” says Mikael Karlsson, professor at the same department.

The researchers also found indications that the same mechanisms are present in humans, including analyses of tumor samples from lung cancer patients who had received immunotherapy.

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Lisa Lock

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Robert Egan

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