Schwann cells promote lung cancer proliferation by promoting the M2 polarization of macrophages

Highlights

• Schwann cells promotes the M2 polarization of macrophages.

• Schwann cell-polarized macrophages increased lung cancer cells prolifertion.

• PNS in the regulation of tumor progression via a “Schwann cell”-“immune cell”-“tumor cell” axis.

Abstract

The interplay between immune cells and tumor cells determines the fate of tumorigenesis. Targeting the abnormal immune response of tumors has been recently achieved great success in some patients. Emerging evidence demonstrated the nervous system plays vital roles in immune regulation, but if the nervous system affects the immune-tumor response and the possible mechanism involved remain largely unexplored. Here, we report that Schwann cells, the major component of the peripheral nervous system (PNS), induce M2 polarization of macrophages by secreting cytokines and chemokines, and these polarized macrophages promote the proliferation of lung cancer cells. We cocultured peripheral blood mononuclear cells (PBMCs) with Schwann cells or treated PBMCs with the culture supernatant of Schwann cells. We found that both treatments induced M2 polarization of the macrophages in peripheral blood mononuclear cell cultures. We performed a bioinformatic analysis of the transcriptome of Schwann cells and analyzed cytokines and chemokines by ELISAs. We found that Schwann cells secreted high levels of CCL2, CXCL5, CXCL12, and CXCL8. CCL2 promotes the M2 polarization of macrophages. Furthermore, we isolated CD14-positive macrophages that were cocultured with the Schwann cells and treated A549 and H1299 lung cancer cells with these macrophages. We found that the Schwann cell-polarized macrophages increased the proliferation of the lung cancer cells. Our study sheds new light on the involvement of the PNS in the regulation of tumor progression via a “Schwann cell”-“immune cell”-“tumor cell” axis.

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.