Induction of immunoregulatory CD271+ cells by metastatic tumor cells that express human endogenous retrovirus H

Chie Kudo-Saito, Masahiro Yura, Ryusuke Yamamoto, Yutaka Kawakami

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 HERVH 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.

Original languageEnglish
Pages (from-to)1361-1370
Number of pages10
JournalCancer Research
Volume74
Issue number5
DOIs
Publication statusPublished - 2014 Mar 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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