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Polarized neutrophils in hepatocellular carcinoma foster immune privilege and disease progression via PD-L1
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Speaker:
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Heng-Hui H.-H. Zhang
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Author:
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G.-X. He1, H. Zhang1*, Y.-H. Chen1, J.-X. Zhou2, X.-W. Xie1, R. Fei1, H. Zeng3, L. Wei1, H.-S. Chen1
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Affiliation:
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1Peking University People’s Hospital, Peking University Hepatology Institute, Beijing, 2Department of Hepatobiliary and Pancreatic Surgery, Henan Tumor Hospital, Zhengzhou, 3Institute of Infectious Diseases, Ditan Hospital, Beijing, China. *zhhbao@163.com
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Background and aims: Neutrophils are the most abundant circulating leukocytes in humans. Recently, dual roles of tumor-associated neutrophils(TANs) within the multiple step paradigm of cancer have been recognized. Although there is the evidence for the existence of N1 (antitumoral) and N2 (protumoral) TANs, similar as M1 and M2 macrophage polarization, it also need to clarify neutrophil effector molecules, such as phenotypic molecular markers, which will contribute to further insights and will be crucial for therapeutical applications in cancer pathologies.
Methods: Peripheral blood and intratumor neutrophils from 110 HCC patients assessed by flow cytometry. Immunocytochemistry were used to analyze the distribution and clinical relevance of neutrophils in 192 HCC patients. For functional analysis, human neutrophils are separated from by flow cytometry sorting and then co-cultured with CD4+/CD8+ effector T cells and tumor-specific antigen inducing CTLs for 48h in vitro. Finally, in vivo analysis, the frequencies and function of neutrophils in peripheral blood. spleen and tumor are evaluated by flow cytometry.
Results: We show here that the expression of programmed death ligand 1(PD-L1), which interacts with PD-1, is increased in neutrophils from HCC patients compared with healthy controls and chronic hepatitis B patients. The expression of PD-L1 was significantly up-regulated on neutrophils after exposure to tumor supernatant from hepatoma cells, and IL-1, IL-6, TNF-αand TGF-βis largely responsible for this up-regulation of PD-L1. Tumor environmental factors induce early transient expression of PD-L1 on neutrophils in tumor bearing mice. The PD-L1+ neutrophils effectively suppressed the proliferation of CD4+/CD8+ effector T cells and tumor-specific T cell immunity, the effect could be reversed by blocking PD-L1 on those neutrophils in vitro. Tumor-bearing increased the frequencies of neutrophils in peripheral blood (mainly G2 population), bone marrow (mainly G3 population), and spleen (mainly G1 population). The infiltrating neutrophils in tumor showed high expression of PD-L1 and infiltrating CD3+ T cells showed high expression of PD-1, compared with peripheral blood and spleen in tumor-bearing mice.
Conclusions: These data suggest that polarized neutrophils in peripheral blood and intratumor of hepatocellular carcinoma with the high expression of PD-L1 may contribute to maintenance of immunosuppression and foster immune privilege.
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