Tumor-associated neutrophils are thought to be immunosuppressive. In Cell, based on single-cell RNA sequencing of 17 cancer types (12 newly generated) from 143 patients, Wu et al. find that neutrophils exhibit diverse transcriptional profiles. Among the 10 states identified (S100A12+, HLA-DR+CD74+, VEGFA+SPP1+, TXNIP+, CXCL8+IL1B+, CXCR2+, IFIT1+ISG15+, MMP9+, NFKBIZ+HIF1A+ and ARG1+ neutrophils), subsets linked to antigen-presentation (HLA-DR+CD74+) and angiogenesis (VEGFA+SPP1+) were most enriched in cancer types, and inflammatory subsets (IFIT1+ISG15+ and NFKBIZ+HIF1A+) were detected in other conditions, such as chronic pancreatitis and COVID-19. VEGFA+SPP1+ neutrophils (enriched in renal cell carcinoma and stomach adenocarcinoma) had increased glycan metabolism and were associated with the worst outcome, whereas HLA-DR+CD74+ neutrophils (enriched in non-small-cell lung cancer, bladder cancer and ovarian cancer) were linked to the best outcome, expressed high levels of CCL5, which recruits T cells, had the highest expression of maturation markers CD11b and CD16, and were enriched in amino acid metabolism. Among 20 amino acids screened, leucine correlated best with the HLA-DR+CD74+ signature, augmented the mitochondrial oxygen consumption rate and enhanced H3K27ac and expression of genes involved in assembly of major histocompatibility complex class II (MHC-II), antigen processing and loading. HLA-DR+CD74+ neutrophils colocalized with CD8+ and CD4+ T cells and seemed to directly activate T cells in vitro through ligand–receptor interactions. Similar neutrophil subsets were detected in seven cancer types in mice. Mice with a conditional deletion (Ly6G-Cre) of MHC-II in neutrophils had increased tumor growth, whereas mice on leucine-rich diet had more CD74+ neutrophils and more T cells in tumors, although similar tumor growth, in two tumor cell transfer models, suggesting neutrophil-linked therapeutic opportunities.
Original reference: Cell 187, 1422–1439.e24 (2024)
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