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

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

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.

T helper cells; CATHELICIDINS; SUPPRESSOR cells; T cells; CELL death; CELL physiology; TRANSFORMING growth factors-beta; WNT signal transduction

Cells (2073-4409), 2020, Vol 9, Issue 6, p1561

2073-4409

Academic Journal

10.3390/cells9061561