A neutrophil response linked to tumor control in immunotherapy II

Neutrophils accumulate in solid tumors and their abundance correlates with poor prognosis. Neutrophils are not homogenous, however, and could play different roles in cancer therapy. Here, we investigated the role of neutrophils in immunotherapy leading to tumor control. We show that successful therapies acutely expanded tumor neutrophil numbers. This expansion could be attributed to a Sell-hi state, rather than to other neutrophils that accelerate tumor 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 antitumor immunity, including BATF3-dependent DCs, IL12 and IFNγ. In addition, we found that a therapy-elicited systemic neutrophil response positively correlated with disease outcome in lung cancer patients. Thus, we establish a crucial role of a neutrophil state in mediating effective cancer therapy. Single cell RNA sequencing (scRNAseq) of CD45-sorted cells from tumors of mice that were treated or not with agonist anti-CD40 immunotherapy. CD45+ cells were sorted from untreated (n=1) and anti-CD40-treated (n=2) tumors.