Cells (Jun 2020)

Cathelicidin-Related Antimicrobial Peptide Regulates CD73 Expression in Mouse Th17 Cells via p38

  • Jeonghyun Lee,
  • Kyong-Oh Shin,
  • Yesol Kim,
  • Jaewon Cho,
  • Hyung W. Lim,
  • Sung-Il Yoon,
  • Geun-Shik Lee,
  • Hyun-Jeong Ko,
  • Pyeung-Hyeun Kim,
  • Yoshikazu Uchida,
  • Kyungho Park,
  • Seung Goo Kang

DOI
https://doi.org/10.3390/cells9061561
Journal volume & issue
Vol. 9, no. 6
p. 1561

Abstract

Read online

The effector function of tumor-infiltrated CD4+ T cells is readily suppressed by many types of immune regulators in the tumor microenvironment, which is one of the major mechanisms of immune tolerance against cancer. Cathelicidin-related antimicrobial peptide (CRAMP), the mouse analog of LL-37 peptide in humans, is a cationic antimicrobial peptide belonging to the cathelicidin family; however, its secretion by cancer cells and role in the tumor microenvironment (TME) remain unclear. In this study, we explored the possibility of an interaction between effector CD4+ T cells and CRAMP using in vitro-generated mouse Th17 cells. We found that CRAMP stimulates Th17 cells to express the ectonucleotidase CD73, while simultaneously inducing cell death. This finding suggested that CD73-expressing Th17 cells may function as immune suppressor cells instead of effector cells. In addition, treatment of pharmacological inhibitors of the transforming growth factor-beta (TGF-β) signaling pathway showed that induction of CD73 expression is mediated by the p38 signaling pathway. Overall, our findings suggest that tumor-derived LL-37 likely functions as an immune suppressor that induces immune tolerance against tumors through shaping effector Th17 cells into suppressor Th17 cells, suggesting a new intervention target to improve cancer immunotherapy.

Keywords