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Orexin A Suppresses the Expression of Exosomal PD-L1 in Colon Cancer and Promotes T Cell Activity by Inhibiting JAK2/STAT3 Signaling Pathway.

Authors
  • Wen, Jing1
  • Chang, Xiaocen1
  • Bai, Bowen2
  • Gao, Qian2
  • Zhao, Yuyan3
  • 1 Department of Endocrinology, Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, Liaoning, China. , (China)
  • 2 Department of Endocrinology, First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning, China. , (China)
  • 3 Department of Endocrinology, First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning, China. [email protected] , (China)
Type
Published Article
Journal
Digestive Diseases and Sciences
Publisher
Springer-Verlag
Publication Date
Jun 01, 2022
Volume
67
Issue
6
Pages
2173–2181
Identifiers
DOI: 10.1007/s10620-021-07077-0
PMID: 34097168
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Colon cancer, ranked third in cancer related mortality, is the most common malignant cancer of digestive tract. Though immune checkpoint inhibitors show promising efficacy in colon cancer, a rather high unresponsive rate and recurrence rate requires further elucidation of the underlying regulatory mechanism of cancer-related immunity. To study the regulatory function of Orexin A in the expression of exosomal PD-L1 and T cell activity. Orthotopic colon cancer transplantation mice model were established to study the cancer growth and immune infiltration between Orexin A treated group and untreated group. In vitro studies using mouse CT-26 and human HCT-116 colon cancer cell model studied the effect of Orexin A on cellular and exosomal PD-L1 expression. Co-culturing Jurkat cells with exosomes delivered by cancer cells treated with Orexin A, PD-L1 knockdown and PBS studied different effects on T cell. Comparing Orexin A with WP1066, a JAK2/STAT3 inhibitor verified the mechanism of these changes. The growth rate of orthotopic transplanted colon cancer was slower in Orexin A treated group, with lower PD-L1 expression and higher immune infiltration. Orexin A could inhibit cellular and exosomal PD-L1 expression. The decreased expression of PD-L1 in exosomes could promote the activity of Jurkat cells secreting higher level of IFN-γ and IL-2. Orexin A showed a similar effect like WP1066 which proved JAK2/STAT3 signaling pathway was its downstream signaling pathway. Orexin A could suppress the expression of exosomal PD-L1 in colon cancer cells and promote T cells activity by inhibiting JAK2/STAT3 signaling pathway. © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

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