Smad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma

Jeff Yat Fai Chung, Philip Chiu Tsun Tang, Max Kam Kwan Chan, Vivian Weiwen Xue, Xiao Ru Huang, Calvin Sze Hang Ng, Dongmei Zhang, Kam Tong Leung, Chun Kwok Wong, Tin Lap Lee, Eric W.F. Lam, David J. Nikolic-Paterson, Ka Fai To, Hui Yao Lan, Patrick Ming Kuen Tang

Research output: Contribution to journalArticleResearchpeer-review

16 Citations (Scopus)

Abstract

Neutrophils are dynamic with their phenotype and function shaped by the microenvironment, such as the N1 antitumor and N2 pro-tumor states within the tumor microenvironment (TME), but its regulation remains undefined. Here we examine TGF-β1/Smad3 signaling in tumor-associated neutrophils (TANs) in non-small cell lung carcinoma (NSCLC) patients. Smad3 activation in N2 TANs is negatively correlate with the N1 population and patient survival. In experimental lung carcinoma, TANs switch from a predominant N2 state in wild-type mice to an N1 state in Smad3-KO mice which associate with enhanced neutrophil infiltration and tumor regression. Neutrophil depletion abrogates the N1 anticancer phenotype in Smad3-KO mice, while adoptive transfer of Smad3-KO neutrophils reproduces this protective effect in wild-type mice. Single-cell analysis uncovers a TAN subset showing a mature N1 phenotype in Smad3-KO TME, whereas wild-type TANs mainly retain an immature N2 state due to Smad3. Mechanistically, TME-induced Smad3 target genes related to cell fate determination to preserve the N2 state of TAN. Importantly, genetic deletion and pharmaceutical inhibition of Smad3 enhance the anticancer capacity of neutrophils against NSCLC via promoting their N1 maturation. Thus, our work suggests that Smad3 signaling in neutrophils may represent a therapeutic target for cancer immunotherapy.

Original languageEnglish
Article number1794
Number of pages17
JournalNature Communications
Volume14
Issue number1
DOIs
Publication statusPublished - 31 Mar 2023

Cite this