Schwann cells promote lung cancer proliferation by promoting the M2 polarization of macrophages
Introduction
The microenvironment of lung cancer is shaped by the complex interactions among tumor cells, immune cells, stromal cells, and vascular cells [1], [2]. Targeting the nontumoral component of the tumor microenvironment, especially components of the exhausted immune response, has also produced therapeutic effects [3], [4]. Recent results from a single-cell transcriptomic analysis of the tumor microenvironment in a lung cancer context demonstrated the abnormal transcriptomic features and functions of immune cells [5], [6]. T cells and macrophages, found in the majority of cancers, lose their antitumor effects. Tumor cells express high levels of PD-L1 and CTAL4 and escape from the T cell immune checkpoints [7], [8]. Macrophages are generally considered the key immune defense cells against invading pathogens and abnormal cells, and these macrophages are identified as M1 type macrophages [9]. Macrophages in the tumor microenvironment lose their antitumor ability and promote the progression of tumor cells, acquiring an M2-like phenotype and expressing cell surface markers CD163 and CD206 [10], [11]. However, the mechanism underlying immune cell dysfunction in the tumor microenvironment remains elusive.
Schwann cells are major components of the peripheral nervous system (PNS) and act as important factors in neural regeneration and repair, in part via the regulation of the immune system [12], [13]. Schwann cells directly respond to injury and recruit immune cells to the injury site by presenting antigens and secreting cytokines and chemokines. Emerging evidence also suggests that Schwann cells are associated with the progression of cancers through mechanisms may be versatile [14], [15], [16], [17]. Schwann cells are usually recognized in supporting tumor development and spreading. Schwann cells have been observed to infiltrate into many types of tumors, including lung cancer [15], pancreatic cancer [16], and melanoma [14]. Several literatures also found that Schwann cells are involved in the suppression of cancer-associated pain and in delayed tumor progression [16], [17]. Our previous studies demonstrated that Schwann cell-secreted CXCL5 interacts with CXCR2 and triggers the activation of the PI3K/AKT/GSK-3β/Snail-Twist pathway in lung cancer cells and promotes the epithelial-mesenchymal transition and metastasis of lung cancer in vivo [15]. We noticed that cytokine CXCL5, produced by Schwann cells, is involved in many other cellular responses, in addition to those directed to tumor cells, especially those reported to have important functions in immune regulation [18], [19], [20], implying that Schwann cells might regulate cancer progression in an indirect manner.
Here, we investigated the function of Schwann cells in the regulation of tumor-associated immune systems and found a novel function of Schwann cells in the regulation of tumor-associated macrophage polarization.
Section snippets
Isolation and culture of peripheral blood mononuclear cells (PBMCs)
PBMCs were isolated with Ficoll-Paque Plus (17144002, GE Healthcare Life Sciences, Little Chalfont, UK) according to the manufacturer’s instructions. The PBMCs were collected from 10 health donors to minimize the batch effects. All of these donors were confirmed to have no acute infection, immune-related disease and systematic disease. All PBMCs were pulled together and stored in liquid nitrogen. Cells were stained with 0.1% Trypan blue dye (GE Healthcare Life Sciences). Positively stained
Schwann cells induced the M2 polarization of the macrophages
To determine the effects of Schwann cells on immune cells, we isolated peripheral blood monocytes (PBMCs) and cocultured them with Schwann cells. After the cells were cocultured for 24 h, we collected the PBMCs and determined the immunotype of the immune cells, including the T cells and macrophages. We first determined the percentage of regulatory T cells in the PBMC fraction cultured with or without Schwann cells. We found that the percentage of regulatory T cells was not changed when the
Discussion
In this study, we report that Schwann cells promoted M2 polarized macrophages via the secretion of CCL2, CXCL5, CXCL12, and CXCL8. We also demonstrated that M2 macrophage polarization by Schwann cells promoted the growth of lung cancer cells.
We found that Schwann cells promoted the M2 polarization of the macrophages in a cell–cell interaction-independent manner. Schwann cells are the initial key regulatory factors in the peripheral nervous system but are also known as immune modulators in
Author contributions
YZ, JL and HZ designed the study and wrote the manuscript. YZ, JL, and RZ performed research work. YZ, JL, and BH analyzed the data. All authors read and approved the final version of the manuscript.
Funding
The study was supported by Shanghai Sailing Program (Grant No. 20YF1444600), the Shanghai Committee of Science and Technology, China (Grant No. 19411970900), Shanghai Chest Hospital Collaborative Innovation Project, China (Grant No. YJXT20190204) and Natural Science Foundation of Shanghai, China (Grant No. 19ZR1449700).
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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These authors contributed equally.