title: 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(+) cells, which included mesenchymal stem cells and myeloid-derived suppressor cells. In tumor tissues from patients with advanced colon cancer, we confirmed that CD271(+) cells were increased in HERV-H(+)CCL19(+) tumor tissues. Notably, RNAi-mediated change of HERV-H or CCL19, or depletion of CD271(+) 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.
authors.affiliation: Authors' Affiliation: Division of Cellular Signalling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Kudo-Saito
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yura
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Yamamoto
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawakami
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D054415:Chemokine CCL19 / Q000235:genetics / Q000276:immunology; D020077:Endogenous Retroviruses / Q000276:immunology*; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000276:immunology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000276:immunology*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics* / Q000276:immunology*; D012191:Retroviridae Proteins / Q000235:genetics* / Q000276:immunology
chemical_list: C515460:CCL19 protein, human; D054415:Chemokine CCL19; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; D012191:Retroviridae Proteins