The power of neutrophils in immunotherapy
SUMMARY
Neutrophils accumulate in solid tumours, and their abundance correlates with poor prognosis. Neutrophils are not homogeneous, however, and could play different roles in cancer therapy. The authors of this study published in Cell, led by Professors Mikael Pittet (UNIGE) and Allon Klein (Harvard University), investigate the role of neutrophils in immunotherapy, leading to tumour control. They show that successful therapies acutely expanded tumour neutrophil numbers. This expansion could be attributed to a Sellhi state rather than to other neutrophils that accelerate tumour progression. Therapy-elicited neutrophils acquired an interferon gene signature, also seen in human patients, and appeared essential for successful therapy, as loss of the interferon-responsive transcription factor IRF1 in neutrophils led to failure of immunotherapy. The neutrophil response depended on key components of anti-tumour immunity, including BATF3-dependent DCs, IL-12, and IFNg. In addition, the authors found that a therapy-elicited systemic neutrophil response positively correlated with disease outcomes in lung cancer patients. Thus, they establish a crucial role of a neutrophil state in mediating effective cancer therapy.
This work was funded by NIH, the ISREC Foundation, Landry Cancer Biology Research, the Swiss National Science Foundation, EMBO, and the Human Frontier Science Program.
Full article: https://doi.org/10.1016/j.cell.2023.02.032
Why is it important?
Neutrophils are the most abundant circulating immune cells in the human body and accumulate in a wide range of cancer types. In mouse models, it has been observed that tumour-infiltrating neutrophils can play both tumour-promoting and anti-tumour roles. The promotion of tumour development has consistently been linked to neutrophils. However, other studies have demonstrated their ability to directly kill cancer cells and stimulate anti-tumour immunity. Much of the biological mechanisms underlying the development of these divergent functional states remain unknown.
By detailing the complexity of neutrophils in the context of mouse therapy, this study reveals that neutrophil-mediated responses are heterogeneous but stereotyped, and include states with critical anti-tumour effects. The authors demonstrate that neutrophils exhibit remarkable plasticity and can acquire an anti-tumour phenotype in response to immunotherapy. Although the treatment-induced neutrophil response may be short-lived, neutrophils may favour the induction of a long-term adaptive immune response. Therefore, cancer immunotherapy approaches that induce anti-tumour T-cell immunity in combination with therapies that optimally engage, rather than deplete, anti-tumour neutrophils could lead to more durable tumour control after treatment.
In French:
Listen to the radio interviews to Prof. Mikael Pittet regarding this work (in French):
Radio Cité Genève: http://rb.gy/hh9g
3 Apr 2023