Interferon-γ Drives Neutrophil PD-L1 Expression, Limiting Cancer Immunotherapy Efficacy
Key Insights
Neutrophils can dampen cancer immunotherapy efficacy by influencing T-cell activity through PD-L1 (search) upregulation, according to preclinical research from Karolinska Institutet published in Immunity.
The study shows that interferon-γ (search) produced by activated immune cells within tumors drives neutrophils to express PD-L1 (search), creating a treatment-induced inhibitory feedback loop.
Genetic deletion of PD-L1 (search) or the interferon-γ (search) receptor on neutrophils made immunotherapy more effective in mouse models of melanoma (search) and breast cancer (search).
Neutrophils can significantly limit the effectiveness of cancer immunotherapy by suppressing T-cell activity, according to new preclinical research from Karolinska Institutet published in Immunity. The findings reveal a previously underappreciated mechanism through which these abundant immune cells undermine treatment response, while also pointing toward combination strategies that may overcome this resistance.
"We see that neutrophils can dampen the effect of immunotherapy by influencing T‑cell activity," said Shengduo Pei, former doctoral student at the Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, and the study's first author.
Neutrophil Depletion Enhances Immunotherapy Response
Researchers analyzed two models of melanoma (search) and breast cancer (search) in both neutropenic mice and mice with normal neutrophil levels to assess how neutrophils impacted response to immunotherapy. The team explored both T-cell and myeloid-cell targeting immunotherapies.
Typical neutrophil levels were consistently associated with reduced efficacy of immunotherapies. Immunotherapies were generally more effective when neutrophils were absent in the mouse models, resulting in a greater immune response and enhanced cytotoxicity. These findings suggest that neutrophil depletion could improve the efficacy of immunotherapies.
Interferon-γ (search) as a Key Driver of Treatment-Induced Resistance
The study also revealed that neutrophils themselves change in response to treatment. When immunotherapy is initiated, neutrophils begin to express PD-L1 (search), a protein that inhibits T-cell activity. This change is driven by the signaling molecule interferon-γ (search), produced by activated immune cells within the tumor.
The researchers demonstrated that this mechanism is cell intrinsic through specific genetic deletion of CD274 (search) (the gene encoding PD-L1 (search)) or IFNGR1 (search) (the interferon-γ (search) receptor) on neutrophils. When the researchers specifically removed PD-L1 or the interferon-γ 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 tumour environment. It also shows the importance of studying blocking mechanisms that arise once treatment begins," said Mikael Karlsson, professor at the same department. "The results may contribute to the development of treatments that combine several therapies to counteract these inhibitory effects."
Translational Relevance in Human Cancer
The researchers also found indications that the same mechanisms are present in humans, including analyses of tumour samples from lung cancer (search) patients who had received immunotherapy. The team is further exploring this mechanism in human patients with lung cancer.
The study was carried out in collaboration with researchers in Sweden, the United States, Germany and China. The research was funded by, among others, the National Institutes of Health, the Swedish Cancer Society and the Swedish Foundation for Strategic Research. The researchers report no conflicts of interest.