Induction of Immunoregulatory CD271+ Cells by Metastatic Tumor Cells That Express Human Endogenous Retrovirus H

Abstract

Human endogenous retroviruses (HERV) are associated with many diseases such as autoimmune diseases and cancer. Although the frequent expression of a variety of HERVs in tumor cells has been demonstrated, their functional contributions in cancer are as yet unclear. Intriguingly, HERVs and other retroviruses include an immunosuppressive domain in their transmembrane envelope proteins, but its mechanism of action and cancer relevance are obscure. In this study, we demonstrate that the human endogenous retrovirus HERV-H has a critical role in tumor metastasis and immune escape. We found that expression of herv-h mRNA was elevated in metastatic tumor cells undergoing epithelial-to-mesenchymal transition (EMT) and in primary tumor tissues from advanced colon cancer. The immunosuppressive peptide H17 derived from HERV-H was sufficient to induce EMT in tumor cells that expressed low levels of HERV-H, and it amplified this event within the tumor microenvironment. H17 also stimulated CCL19 expression in tumor cells, which in turn recruited and expanded a population of pluripotent immunoregulatory CD271 þ cells, which included mesenchymal stem cells and myeloid-derived suppressor cells. In tumor tissues from patients with advanced colon cancer, we confirmed that CD271 þ cells were increased in HERV-H þ CCL19 þ tumor tissues. Notably, RNAi-mediated change of HERV-H or CCL19, or depletion of CD271 þ cells, improved immune responses in vitro and in vivo accompanied by tumor regression. Together, our results argued that HERV-H is a critical determinant of immune escape in cancer, suggesting its candidacy as a promising therapeutic target to treat patients with advanced cancer.

Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth

“…In another study, HERV-H was reported to be expressed in 2 of 12 PCs, with little expression in some normal tissues (63). However, HERV-H was expressed in normal pancreas tissue (64). …”

Expressional activation and functional roles of human endogenous retroviruses in cancers

“…Infection of murine ERV‐env expression vector presenting the envelope immunosuppressive domain into cancer cells promoted tumor growth in vivo by preventing the activity of innate immune system that clears tumors . The immunosuppressive peptide H17, deriving from HERV‐H, was recently identified to induce epithelial‐mesenchymal transition and stimulate expression of the chemokine CCL19 in tumor cells …”

“…131 The immunosuppressive peptide H17, deriving from HERV-H, was recently identified to induce epithelial-mesenchymal transition and stimulate expression of the chemokine CCL19 in tumor cells. 132 In recent years, epigenetic therapies are under active investigation in diverse solid tumors, inducing immune responses and reactivating silenced tumor suppressors. 133,134 It has been shown that low doses of DNA methylation inhibitors 5-aza-2′-deoxycytidine (decitabine) or CDK4/6 inhibitors can induce the transcription of HERV-derived double-stranded RNAs (dsRNAs) and IFN-response genes in tumor cells.…”

Antigenicity of peptides comprising the immunosuppressive domain of the retroviral envelope glycoprotein

“…Several studies over the last three decades have provided evidence to suggest that the envelope glycoprotein of certain retroviruses is immunosuppressive in vitro and in vivo (Cianciolo et al, 1985; de Parseval et al, 2001; Denner, 2014; Dupressoir et al, 2012; Haraguchi et al, 1997; Kudo-Saito et al, 2014; Mangeney et al, 2007; Schlecht-Louf et al, 2010). Although the precise molecular mechanism remains unresolved, immunosuppressive activity has been pinpointed at a short region of the transmembrane polypeptide that, together with the surface unit (SU), constitutes one part of the trimeric envelope glycoprotein (Cianciolo et al, 1985; Dupressoir et al, 2012; Schlecht-Louf et al, 2010).…”