IL10R Inhibition Induces Neutrophil Tumoricidal Activity
Access to this document is restricted. Some items have been embargoed at the request of the author, but will be made publicly available after the "No Access Until" date.
During the embargo period, you may request access to the item by clicking the link to the restricted file(s) and completing the request form. If we have contact information for a Cornell author, we will contact the author and request permission to provide access. If we do not have contact information for a Cornell author, or the author denies or does not respond to our inquiry, we will not be able to provide access. For more information, review our policies for restricted content.
While the role of neutrophils in modulating antitumor T cell responses has been extensively studied, their direct effects on tumor cells remains less well understood. In this study, we investigated whether neutrophils have the capacity to directly kill tumor cells independently of T cells. We found that anti-CD40-based therapy, when combined with interleukin 10 (IL-10) receptor blockade initiates a Batf3-dependent pathway in which IL-12 and interferon gamma (IFNγ) secretion results in oncolytic neutrophil activity. Using a combination of microscopy, single-cell, and functional assays, we observed that killing of tumor cells by neutrophils is dependent on physical contact and degranulation. This degranulation-mediated killing is associated with an atypical dynamic invasive neutrophil phenotype. In line with our preclinical findings, our phase 1 trial of anti-CD40 shows that circulating IL-12, IFNγ, and IL-10 increase in response to anti-CD40, while our phase 1b/2 PRINCE study shows that lower circulating IL-10 is associated with favorable overall survival specifically among anti-CD40-treated patients. Finally, we found that neutrophil expansion with granulocyte colony stimulating factor (G-CSF) is associated with improved overall survival, specifically in patients treated with anti-CD40, suggesting that this pathway may be amenable to therapeutic intervention in patients with advanced cancer.