A subset of neutrophils activates anti-tumor immunity and inhibits non-small-cell lung cancer progression

Neutrophils in the tumor microenvironment (TME) are heterogeneous populations associated with cancer prognosis and immunotherapy. However, the plasticity and function of heterogeneous neutrophils in the TME of non-small-cell lung cancer (NSCLC) remain unclear. Here, we show that neutrophils produce high levels of interleukin (IL)-8, which induce the differentiation of CD74^highSiglecF^low neutrophils and suppress the generation of CD74^lowSiglecF^high neutrophils in the TME of IL-8-humanized NSCLC mice. The CD74^highSiglecF^low neutrophils boost anti-tumor T cell responses via antigen cross-presentation. Deleting CD74 in IL-8-humanized neutrophils impairs T cell activation and exacerbates NSCLC progression, whereas a CD74 agonist enhances T cell activation and the efficacy of anti-programmed cell death 1 (PD-1) or osimertinib therapies. Additionally, the CD74^highCD63^low neutrophils in the TME and peripheral blood of advanced NSCLC patients phenocopy the CD74^highSiglecF^low neutrophils in the TME of NSCLC mice and correlate well with the responsiveness to anti-PD-1 plus chemotherapies. These findings demonstrate an IL-8-CD74^high neutrophil axis that promotes anti-tumor immunity in NSCLC.