Tumor Induced PD-L1 on Neutrophils Suppress the Antitumor Immunity of NK Cells via PD-L1/PD-1 Axis

Abstract

In tumor-bearing state, the conversion of the system immune status makes the protumor function of neutrophils, and leading the suppression of NK cells cytotoxicity. The induced dysfunctional neutrophils could modulate the antitumor function of NK cells, but it is unclear whether and how the rebellious neutrophils modulate the NK cells anti-tumor function. Here we report that tumor-bearing neutrophils could impair NK cells cytotoxicity and the infiltration capability. Decreased CCR1 responsible for the weakened infiltration capability. Neutrophils could decrease the reactivity of NK activating receptor NKp46 and NKG2D. Induced PD-L1 expression (neutrophils) and PD-1 (NK cells) and the PD-L1/PD-1 axis were the main one mechanism of the suppression of NK cells immunity. Systemic increased G-CSF enhanced the expression of PD-L1, G-CSF/JAK2-STAT3 cell signaling pathway responsible to the upregulation of PD-L1. Tumor derived IL-18 enhances the PD-1 expression, block the IL-18 pathway by IL-18BP or knockdown the IL-18 expression by siRNA could both offset the IL-18 induced PD-1 expression. The neutrophils and NK cells crosstalk was cell-cell contact dependent, the affect of neutrophils on NK cells was disappeared when they were cultured in a separate system. These findings highlight the PD-L1/PD-1 signal on the immune suppression effect of neutrophils on NK cells. G-CSF and IL-18 producing might lead to a poor prognosis via different ways which cooperate to activate the immunosuppressive signal and weaken the antitumor affect of NK cells. Targeting G-CSF and IL-18 might be a potential approach to eliminate residual tumor cells in comprehensive strategy for tumor therapy. Funding Statement: This work was supported by National Natural Science Foundation of China (No. 81502461, 81502265), Natural Science Foundation of Hubei province (NO. 2016CFB340), Key Project of Wuhan Municipal Health Planning Commission Key Project (NO. WX15A08). Huazhong University of Science and Technology Double Top Construction, Project of International Cooperation (NO. 540-5001540013). Declaration of Interests: No potential conflicts of interest were disclosed. Ethics Approval Statement: BALB/c mice, 6 wks old, were purchased from Center of Medical Experimental Animals of Hubei Province (Wuhan, China) for studies approved by the Animal Care and Use Committee of Tongji Medical College (Wuhan, China).