Neutrophils Create an ImpeNETrable Shield between Tumor and Cytotoxic Immune Cells

Abstract

Neutrophil extracellular traps (NETs) can promote tumor growth and metastases, but whether NETs impact the tumor immune microenvironment remains underexplored. In this issue of Immunity, Teijeira et al. discover that NETs shield tumor cells from cytotoxic immune cells, resulting in impaired tumor clearance.

Figure 1.. Neutrophil Extracellular Traps Shield Tumor Cells from the Effects of Cytotoxic Immune Cells and Immunotherapies.

Human neutrophils form neutrophil extracellular traps (NETs) following activation of CXCR1 and −2 receptors by chemokines secreted by tumor cells, including IL-8 and CXCL-1, −2, and −8 (top left). NETs shield tumor cells from the cytotoxic effects of anti-tumor immune cells—specifically NK cells and CD8⁺ T cells—which can result in increased tumor growth (top right). Blocking NET formation via pharmacological PAD4 inhibitors, DNAse-I, Pertussis-toxin (Ptx), or CXCR1 and −2 inhibitors allows tumor cell contact with cytotoxic immune cells. Teijeira et al. demonstrate NETosis blockade by PAD4 inhibition can increase the efficacy of anti-PD1 plus anti-CTLA4 immune checkpoint inhibitors—highlighting exciting potential for a new therapeutic strategy where NET blockade maximizes the effect of immunotherapy.