Researchers have discovered that the type II interferon, interferon-γ, may impact how neutrophils react to immunotherapy, either supporting or blocking the treatment for patients with cancer, according to study findings published in Immunity.
Study Methods and Key Findings
Researchers analyzed two models of melanoma and breast cancer in both neutropenic mice and mice with normal neutrophil levels to assess how neutrophils impacted response to immunotherapy. They explored the use of both T-cell and myeloid-cell targeting immunotherapies.
Typical neutrophil levels were associated with reduced efficacy of immunotherapies, but the study authors suggested that neutrophil depletion could improve the efficacy of immunotherapies.
“We see that neutrophils can dampen the effect of immunotherapy by influencing T‑cell activity,” stated first study author Shengduo Pei, a former doctoral student in the Department of Microbiology, Tumor, and Cell Biology at Karolinska Institutet, Stockholm, Sweden.
When treated with immunotherapy, neutrophils upregulated PD-L1, driven by interferon-γ from cytotoxic lymphocytes, and used the expression as a target to deplete the population. The researchers demonstrated that this was cell intrinsic due to specific genetic deletion of CD274 or LFNGR1 on neutrophils.
Immunotherapies were generally more effective when there was an absence of neutrophils in the mouse models, resulting in a greater immune response and cytotoxicity. When researchers deleted PD-L1 or the interferon-γ receptor, neutrophils became more sensitive to immunotherapy.
“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,” said Mikael Karlsson, PhD, Professor of Immunology in the Department of Microbiology, Tumor, and Cell Biology at Karolinska Institutet "The results may contribute to the development of treatments that combine several therapies to counteract these inhibitory effects."
The researchers are further exploring this mechanism in human patients with lung cancer.
DISCLOSURES: 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.
