AUTHOR=Shen Chunyi , Liu Chaojun , Zhang Zhen , Ping Yu , Shao Jingwen , Tian Yonggui , Yu Weina , Qin Guohui , Liu Shasha , Wang Liping , Zhang Yi 

TITLE=PD-1 Affects the Immunosuppressive Function of Group 2 Innate Lymphoid Cells in Human Non-Small Cell Lung Cancer

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.680055

DOI=10.3389/fimmu.2021.680055

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>There is increasing evidence that group 2 innate lymphoid cells (ILC2s) play an essential role in allergy and parasitic infection. However, the role of ILC2s in human lung cancer remains unclear.</p></sec><sec><title>Methods</title><p>ILC2s from peripheral blood mononuclear cells (PBMCs) obtained from healthy donors (HDs) and non-small cell lung cancer (NSCLC) patients, and NSCLC tumor tissues were analyzed <italic>via</italic> multicolor flow cytometry. ILC2s or CD14<sup>+</sup> cells were sorted by fluorescence-activated cell sorting. qPCR and flow cytometry were performed to assess the gene and protein expression of the indicated molecules. M1-like and M2-like macrophages were induced from CD14<sup>+</sup> monocytes <italic>in vitro</italic>.</p></sec><sec><title>Results</title><p>ILC2s were significantly more enriched in PBMCs and tumor tissues from NSCLC patients than in HDs. After screening for the main immune checkpoint molecules, we found that PD-1 was upregulated in ILC2s in NSCLC patients. Functionally, PD-1<sup>high</sup> ILC2s from tumor tissues expressed higher levels of IL-4 and IL-13 regarding both mRNA and protein levels than PD-1<sup>low</sup> ILC2s. Furthermore, PD-1<sup>high</sup> ILC2s robustly boosted M2-like macrophage polarization <italic>in vitro</italic>, by secreting IL-4 and IL-13, while neutralization of IL-4 and IL-13 by antibodies abrogated M2-like macrophage polarization.</p></sec><sec><title>Conclusion</title><p>ILC2s are enriched in NSCLC patients and upregulate PD-1 expression. Upregulation of PD-1 facilitates the immunosuppressive function of ILC2s. PD-1<sup>high</sup> ILC2s enhance M2-like macrophage polarization by secreting IL-4 and IL-13. PD-1 acts as a positive regulator of the immunosuppressive function of ILC2s in human NSCLC.</p></sec>