Using IL-8hu models of NSCLC, Tang et al. found that IL-8 controlled tumor growth, and CD74hiSiglec6lo neutrophils emerged in response to IL-8 signaling. In vivo, this subset exhibited antigen cross-presentation capacity and superior T cell stimulation. CD74 KO ablated tumor control in IL-8 mice, reduced neutrophil MHC/CD86, and impaired T cell activation. Conversely, CD74 agonism slowed tumor growth in IL-8 mice alone and with anti-PD-L1 or osimertinib. A putative analogous human subset (CD74hiCD63lo) could be induced by IL-8 in vitro, exhibited superior T cell stimulation, and was more abundant in the blood of responders to ICB in NSCLC.
Contributed by Morgan Janes
ABSTRACT: 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 CD74highSiglecFlow neutrophils and suppress the generation of CD74lowSiglecFhigh neutrophils in the TME of IL-8-humanized NSCLC mice. The CD74highSiglecFlow 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 CD74highCD63low neutrophils in the TME and peripheral blood of advanced NSCLC patients phenocopy the CD74highSiglecFlow 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-CD74high neutrophil axis that promotes anti-tumor immunity in NSCLC.
Author Info: (1) Department of Gastrointestinal Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan Universit
Author Info: (1) Department of Gastrointestinal Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China (2) Department of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China (3) Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China (4) Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China (5) Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, China (6) TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China
