Netrin-1 Promotes the Immunosuppressive Activity of MDSCs in Colorectal Cancer

Abstract

Myeloid-derived suppressive cells (MDSCs) inhibit antitumor immunity and confer a survival advantage for tumor evasion. Tumor cells also support MDSC expansion and recruitment by secreting multiple growth factors and cytokines, but the mechanisms by which tumors affect MDSC function are not completely understood. Here, we found that the neuronal guidance protein netrin-1 was selectively secreted by MC38 murine colon cancer cells, which could enhance the immunosuppressive activity of MDSCs. MDSCs predominantly expressed one type of netrin-1 receptor, adenosine receptor 2B (A2BR). Netrin-1 interacted with A2BR on MDSCs to activate the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway, which ultimately increased CREB phosphorylation in MDSCs. Furthermore, netrin-1 knockdown in tumor cells inhibited the immunosuppressive activity of MDSCs and restored antitumor immunity in MC38 tumor xenograft mice. Intriguingly, high netrin-1 in the plasma correlated with MDSCs in CRC patients. In conclusion, netrin-1 significantly enhanced the immunosuppressive function of MDSCs through A2BR on MDSCs, thus promoting the development of tumors. These findings highlight that netrin-1 may regulate the abnormal immune response in colorectal cancer and may become a potential target for immunotherapy.

HIF‐1α targeted deletion in myeloid cells decreases MDSC accumulation and alters microbiome in neonatal mice

“…In addition, MDSCs are known to express ectonucleotidases that contribute to the formation of adenosine in a HIF-1α dependent pathway [80]. Moreover, very recently, netrin-1 was shown to increase the suppressive activity of MDSC [81], so that decreased netrin-1 levels in Hif1a loxP/loxP LysM Cre+ mice could potentially have an effect on MDSC functionality. However, these considerations are pure speculation here and require further investigation.…”

Research progress of the netrins and their receptors in cancer

“… 113 NTN1 knockdown in tumour cells decreased the immunosuppressive activity of myeloid‐derived suppressive cells (MDSCs) and restored antitumor immunity in MC38 tumour xenograft mice, according to Xia et al. 116 The molecular mechanism investigation revealed that NTN1 significantly enhanced the immunosuppressive function of MDSCs through A2BR on MDSCs, thus promoting the development of tumours. In addition, Ducarouge et al.…”

“…Pten f/f EC mice treated with NP137 had an increase in CD8 + cells. 113 NTN1 knockdown in tumour cells decreased the immunosuppressive activity of myeloid-derived suppressive cells (MDSCs) and restored antitumor immunity in MC38 tumour xenograft mice, according to Xia et al 116 The molecular mechanism investigation revealed that NTN1 significantly enhanced the immunosuppressive function of MDSCs through A2BR on MDSCs, thus promoting the development of tumours. In addition, Ducarouge et al 117 discovered that NTN1 interference limits tumour resistance to immune checkpoint inhibitors and provided evidence linking this enhanced anti-tumour efficacy to a decreased recruitment of a subtype of MDSCs called polymorphonuclear (PMN)-MDSCs.…”

ALKBH5 regulates arginase 1 expression in MDSCs and their immunosuppressive activity in tumor-bearing host

“…Studies have proven that excessive amounts of circulating MDSCs are closely related to poor prognosis, tumor angiogenesis, and tumor evasion immunity [ 4 ]. This reveals a new regulatory mechanism of tumor growth and provides a new research direction for tumor therapy [ 5 ].…”