2022, Pylaeva, Ekaterina, Korschunow, Georg, Spyra, Ilona, Bordbari, Sharareh, Siakaeva, Elena, Ozel, Irem, Domnich, Maksim, Squire, Anthony, Hasenberg, Anja, Thangavelu, Kruthika, Hussain, Timon, Goetz, Moritz, Lang, Karl S, Gunzer, Matthias, Hansen, Wiebke, Buer, Jan, Bankfalvi, Agnes, Lang, Stephan, Jablonska, Jadwiga

Tumor-draining lymph nodes (LNs) play a crucial role during cancer spread and in initiation of anti-cancer adaptive immunity. Neutrophils form a substantial population of cells in LNs with poorly understood functions. Here, we demonstrate that, during head and neck cancer (HNC) progression, tumor-associated neutrophils transmigrate to LNs and shape anti-tumor responses in a stage-dependent manner. In metastasis-free stages (N0), neutrophils develop an antigen-presenting phenotype (HLA-DR+CD80+CD86+ICAM1+PD-L1-) and stimulate T cells (CD27+Ki67highPD-1-). LN metastases release GM-CSF and via STAT3 trigger development of PD-L1+ immunosuppressive neutrophils, which repress T cell responses. The accumulation of neutrophils in T cell-rich zones of LNs in N0 constitutes a positive predictor for 5-year survival, while increased numbers of neutrophils in LNs of N1-3 stages predict poor prognosis in HNC. These results suggest a dual role of neutrophils as essential regulators of anti-cancer immunity in LNs and argue for approaches fostering immunostimulatory activity of these cells during cancer therapy.