Schwann cells shape the neuro-immune environs and control cancer progression

Abstract

At present, significant experimental and clinical data confirm the active involvement of the peripheral nervous system (PNS) in different phases of cancer development and progression. Most of the research effort focuses on the impact of distinct neuronal types, e.g., adrenergic, cholinergic, dopaminergic, etc. in carcinogenesis, generally ignoring neuroglia. The very fact that these cells far outnumber the other cellular types may also play an important role worthy of study in this context. The most prevalent neuroglia within the PNS consists of Schwann cells (SCs). These cells play a substantial role in maintaining homeostasis within the nervous system. They possess distinct immunomodulatory, inflammatory and regenerative capacities-also, one should consider their broad distribution throughout the body; this makes them a perfect target for malignant cells during the initial stages of cancer development and the very formation of the tumor microenvironment itself. We show that SCs in the tumor milieu attract different subsets of immune regulators and augment their ability to suppress effector T cells. SCs may also up-regulate invasiveness of tumor cells and support metastatic disease. We outline the interactive potential of SCs juxtaposed with cancerous cells, referring to data from various external sources alongside data of our own.

Keywords: Cancer; MDSC; Neuroglia; PIVAC 18; Schwann cells; Tumor microenvironment.

Fig. 1

Melanoma-activated Schwann cells chemoattract MDSC in vitro. Adult Schwann cells were isolated from sciatic nerve of C57BL/6 mice, purified and cultured as described [101]. Cells were then co-cultured with cell culture medium (see [101]) (Schwann/cntr) and B16 melanoma cells (Schwann/B16) in inserts (2:1 cell ratio) for 48 h and washed. Then, control and B16-pretreated Schwann cells were co-cultured with membrane-separated (5 µm pore size) bone marrow-derived MDSC (upper chamber) for 6 h, and the number of transmigrated CD11b + Gr-1 + MDSC in the bottom chamber was determined by flow cytometry for 60 s (n = 3; *p < 0.05 versus control Schwann cells, ANOVA). Results are shown as the mean ± SEM. SDF-1α (5 ng/ml) was used as a positive control. MDSC, myeloid-derived suppressor cells; SDF-1α, Stromal cell-derived factor 1 (CXCL12)

Fig. 2

Melanoma up-regulates expression of MAG in Schwann cells. Primary mouse adult Schwann cells were prepared as described in Fig. 1 legend and co-cultured with control medium (Schwann/cntr) and B16 melanoma cells (Schwann/B16) in inserts (48 h). Cells were then isolated, washed and expression of MAG mRNA was determined by qRT-PCR (left) and MAG protein by flow cytometry (right). RPLP0 (Ribosomal Protein Lateral Stalk Subunit P0) served as a housekeeping control (*p < 0.01, Student t test, n = 3). Results are shown as the mean ± SEM (right). The flow cytometry results of a representative experiment are shown (right). MAG, myelin-associated glycoprotein

Fig. 3

Both melanoma-treated Schwann cells and MAG increase the immune suppressive potential of MDSC. Isolated splenic T cells were activated with CD3/CD28 beads (T cntr), cultured with differentially treated bone marrow-derived MDSC for 72 h and T cell proliferation was assessed by ³H-thymidine incorporation. MDSC, control MDSC; MDSC/MAG, MDSC pre-treated with 0.5 and 5.0 µg/ml MAG; MDSC/SC and MDSC/SC + B16, MDSC pre-treated with control or B16-treated Schwann cells. Schwann cells and MDSC were isolated and cultured as described in Fig. 1 legend. Results are shown as the mean ± SEM. *p < 0.01 versus a corresponding MDSC control (n = 3). T0 non-activated T cells; cpm, counts per minute, SC Schwann cells, MDSC myeloid-derived suppressor cells, MAG myelin-associated glycoprotein