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
Affiliations
Jeonghyun Lee
Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Korea
Kyong-Oh Shin
Department of Food Science and Nutrition, and Convergence Program of Material Science for Medicine and Pharmaceutics, Hallym University, Chuncheon 24252, Korea
Yesol Kim
Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Korea
Jaewon Cho
College of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
Hyung W. Lim
Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medicine, Department of Neurology, University of California, San Francisco, CA 94158, USA
Sung-Il Yoon
Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Korea
Geun-Shik Lee
Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341, Korea
Hyun-Jeong Ko
College of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
Pyeung-Hyeun Kim
Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon 24341, Korea
Yoshikazu Uchida
Department of Dermatology, School of Medicine, University of California, San Francisco and Northern California Institute for Research and Education, Veterans Affairs Medical Center, San Francisco, CA 94212, USA
Kyungho Park
Department of Food Science and Nutrition, and Convergence Program of Material Science for Medicine and Pharmaceutics, Hallym University, Chuncheon 24252, Korea
Seung Goo Kang
Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Korea
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.