Tumor associated neutrophils governs tumor progression through an IL-10/STAT3/PD-L1 feedback signaling loop in lung cancer

Abstract

Tumor-associated neutrophils (TANs) can exist in either a pro-inflammatory or an anti-inflammatory state, known as N1 and N2, respectively. Anti-inflammatory TANs have been shown to correlate with poor prognosis and tumor progression in patients. To explore the role and mechanisms of TANs in lung cancer development, we isolated neutrophils from both peripheral blood and tumor tissues of patients/mice, and assessed their functional interaction with lung cancer cells both in vitro and in vivo. Our results revealed that tumor-derived neutrophils (or TANs) promote the tumorigenic and metastatic potential of lung cancer cells. Upon tumorigenesis, TANs display a N2-like status and secrete the cytokine IL-10 to facilitate the activation of c-Met/STAT3 signaling, which ultimately enhances distant metastasis in vivo. Meanwhile, the transcription factor STAT3 increases PD-L1 level in tumor cells, which promotes neutrophils polarization towards a N2-like status, leading to a positive feedback loop between TANs, IL-10, STAT3, PD-L1, and TANs themselves. Blocking IL-10, we additionally eliminated metastatic tumor nodules and enhanced the anticancer effects of chemotherapy in a Lewis mouse model. Our findings suggest a positive feedback loop between tumor cells and TANs that controls tumor progression and patient outcome in lung cancer.