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 and Patrick Ming-Kuen Tang ()
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Jeff Yat-Fai Chung: The Chinese University of Hong Kong
Philip Chiu-Tsun Tang: The Chinese University of Hong Kong
Max Kam-Kwan Chan: The Chinese University of Hong Kong
Vivian Weiwen Xue: The Chinese University of Hong Kong
Xiao-Ru Huang: The Chinese University of Hong Kong
Calvin Sze-Hang Ng: The Chinese University of Hong Kong
Dongmei Zhang: Jinan University
Kam-Tong Leung: The Chinese University of Hong Kong
Chun-Kwok Wong: The Chinese University of Hong Kong
Tin-Lap Lee: The Chinese University of Hong Kong
Eric W-F Lam: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
David J. Nikolic-Paterson: Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre
Ka-Fai To: The Chinese University of Hong Kong
Hui-Yao Lan: The Chinese University of Hong Kong
Patrick Ming-Kuen Tang: The Chinese University of Hong Kong

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37515-8

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