Tyrosine kinase inhibitors modulate dendritic cell activity via confining c-Kit signaling and tryptophan metabolism

Ching-Liang Chu; Yi-Pang Lee; Cheng-Yoong Pang; Huei-Ru Lin; Chang-Shan Chen; Ren-In You

doi:10.1016/j.intimp.2020.106357

Tyrosine kinase inhibitors modulate dendritic cell activity via confining c-Kit signaling and tryptophan metabolism

Int Immunopharmacol. 2020 Mar 6:82:106357. doi: 10.1016/j.intimp.2020.106357. Online ahead of print.

Authors

Ching-Liang Chu¹, Yi-Pang Lee², Cheng-Yoong Pang³, Huei-Ru Lin⁴, Chang-Shan Chen⁵, Ren-In You⁶

Affiliations

¹ Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Department of Health Administration, Tzu Chi University of Science and Technology, Hualien, Taiwan; Division of Oral Pathology, Department of Dentistry, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
³ Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan; Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
⁴ Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan.
⁵ Institutes of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
⁶ Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan. Electronic address: yri100@gms.tcu.edu.tw.

PMID: 32151959
DOI: 10.1016/j.intimp.2020.106357

Abstract

Dendritic cell (DC)-based vaccine has been established in tumor immunotherapy. Importantly, the efficiency of anti-tumor T-cells in draining lymph nodes is dependent on the status of DCs surrounding in tumors. It has been shown that Indoleamine 2,3-dioxygenase (IDO) plays a key role to induce tolerogenic DCs in tumor microenvironment, and tyrosine kinase inhibitors (TKIs) can suppress the function of IDO in DCs. However, the stimulatory effect of TKI-modified DCs on T cells remains unclear. In this report, we found that one type of TKI-dasatinib can modify DCs to increasing the activation of allogenic T cells. These TKI-modified DCs delayed the onset of B16 melanoma progression in mice. In mechanistic studies, TKIs did not increase the maturation but reduce the expression and phosphorylation levels of IDO and IDO mediated tryptophan metabolism in DCs. In addition, the suppressive effect of TKIs on tryptophan metabolism may be caused by blocking c-Kit pathway in DCs. Furthermore, the increased phosphorylation of general control nonderepressible (GCN2) and decreased expression of aryl hydrocarbon receptor (AhR)/aryl hydrocarbon receptor nuclear translocator (ARNT) were observed in the T cells activated by TKI-modified DCs, suggesting the enhancement of effector function of T cells. These results indicate that TKI could be used to modulate DC immunogenic activity and may potentially be applied in DC-based cancer immunotherapy.

Keywords: 3-dioxygenase; Dendritic cells; Indoleamine-2; Tryptophan metabolism; Tyrosine kinase inhibitors; c-Kit.