The functional role of tumor-associated neutrophils (TAN) in cancer progression is still controversial and largely unknown. Interestingly, Smad3-deficiency markedly increases TANs population in a syngeneic lung carcinoma mouse model LLC. We hypothesize that TGF-β1/Smad3 signaling may play an important role in TAN regulation and its function.
To investigate that heterogeneity and transcriptomic dynamics of TAN within Smad3 TME, we used 10x single-cell RNA-sequencing and gene ontology analysis. The ChiP-sequencing help to discover novel Smad3 mechanistic target gene in TAN under cancer condition. Future more, both in vitro and in vivo study were included to uncover the function of TAN in the Smad3-depedent TME.
Surprisingly, we found several novel TAN subsets in the Smad3-null TME which were highly distinct to the wildtype TAN in the neutrophil-specific 10x single-cell RNA-sequencing. Gene ontology analysis suggested transcriptomes of the wildtype TAN were highly associated with cell cycle arrest and senescence; supporting by the prolonged lifespan of the Smad3-KO TAN in vitro and in vivo. Mechanistically, ChIP-sequencing discovered a quiescence mediator Prdm2 as a novel Smad3 direct target gene in TAN under cancer condition in vitro and in vivo, which significantly associated with NSCLC mortality. More importantly, adoptive transfer of Prdm2-silenced bone marrow derived neutrophils markedly inhibited the progression of LLC-tumor in mice.
We discovered Prdm2 as a Smad3-dependent immunosuppressor of TAN, which may represent as a novel therapeutic target for cancer.
Legal entity responsible for the study
Research Grants Council of Hong Kong, The Chinese University of Hong Kong.
All authors have declared no conflicts of interest.