Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer
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Jayati Chakrabarti1, Loryn Holokai2, LiJyun Syu3, Nina G. Steele4, Julie Chang5, Jiang Wang6, Syed Ahmed7, Andrzej Dlugosz3,8 and Yana Zavros1
1Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH, USA
2Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, OH, USA
3Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
4Division of Developmental Biology, University of Michigan, Ann Arbor, MI, USA
5Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH, USA
6Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
7Department of Surgery, University of Cincinnati Cancer Institute, Cincinnati, OH, USA
8Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
Yana Zavros, email: firstname.lastname@example.org
Keywords: gastric cancer organoids, PD-1; cytotoxic T lymphocytes; dendritic cells
Received: August 29, 2018 Accepted: November 26, 2018 Published: December 21, 2018
Tumor cells expressing programmed cell death ligand 1 (PD-L1) interact with PD-1 on CD8+ cytotoxic T lymphocytes (CTLs) to inhibit CTL effector function. In gastric cancer, the mechanism regulating PD-L1 is unclear. The Hedgehog (Hh) signaling pathway is reactivated in various cancers including gastric. Here we tested the hypothesis that Hh-induced PD-L1 inactivates effector T cell function and allows gastric cancer cell proliferation. Mouse organoids were generated from tumors of a triple-transgenic mouse model engineered to express an activated GLI2 allele, GLI2A, in Lgr5-expressing stem cells, (mTGOs) or normal mouse stomachs (mGOs). Bone marrow-derived dendritic cells (DCs) were pulsed with conditioned media collected from normal (mGOCM) or cancer (mTGOCM) organoids. Pulsed DCs and CTLs were then co-cultured with either mGOs or mTGOs in the presence of PD-L1 neutralizing antibody (PD-L1Ab). Human-derived gastric cancer organoids (huTGOs) were used in drug and xenograft assays. Hh/Gli inhibitor, GANT-61 significantly reduced the expression of PD-L1 and tumor cell proliferation both in vivo and in vitro. PD-L1Ab treatment induced tumor cell apoptosis in mTGO/immune cell co-cultures. GANT-61 treatment sensitized huTGOs to standard-of-care chemotherapeutic drugs both in vivo and in vitro. Thus, Hh signaling mediates PD-L1 expression in gastric cancer cells and subsequently promotes tumor proliferation.
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