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Increase of Tumor Infiltrating γδ T-cells in Pancreatic Ductal Adenocarcinoma Through Remodeling of the Extracellular Matrix by a Hyaluronan Synthesis Suppressor, 4-Methylumbelliferone

Suto, Akiko, MD*; Kudo, Daisuke, MD, PhD*; Yoshida, Eri, MD, PhD*; Nagase, Hayato, MD, PhD*; Suto, Shinichiro, PhD; Mimura, Junsei, PhD; Itoh, Ken, MD, PhD; Hakamada, Kenichi, MD, PhD*

doi: 10.1097/MPA.0000000000001211
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Objectives Desmoplastic changes of extracellular matrix (ECM) containing large amounts of hyaluronan (HA) are of interest in chemo- and immunoresistance of pancreatic ductal adenocarcinoma (PDAC). The goal of this study was to evaluate the effects of 4-methylumbelliferone (MU), a selective inhibitor of HA, on ECM and to examine how MU affects adoptive immunotherapy.

Methods The effect of MU on cell proliferation, HA synthesis and formation of ECM were investigated in four PDAC cell lines. In addition, the cytotoxicity of γδ T-cell-rich peripheral blood mononuclear cells (PBMCs) collected from healthy donors and stimulated with zoledronate and interleukin-2 was examined in the presence of MU. The amount of HA and tumor-infiltrating lymphocytes were also investigated in mice xenograft models.

Results In vitro, 1.0 mM MU inhibited cell proliferation by 45–70% and HA synthesis by 55–80% in all four PDAC cell lines, and enhanced γδ T-cell-rich PBMC-mediated cytotoxicity against PDAC cells. In vivo, MU reduced intratumoral HA and promoted infiltration of inoculated γδ T-cells into tumor tissue, and consequently suppressed tumor growth.

Conclusions 4-methylumbelliferone may be an effective immunosensitizer against PDAC through induction of structural changes in the ECM.

From the Departments of *Gastroenterological Surgery,

Glycotechnology, and

Stress Response Science, Hirosaki University, Graduate School of Medicine, Hirosaki, Japan.

Received for publication May 2, 2018; accepted October 29, 2018.

Address correspondence to: Kenichi Hakamada, MD, PhD, Department of Gastroenterological Surgery, Hirosaki University, Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, Japan 036–8562 (e-mail: hakamada@hirosaki-u.ac.jp).

The authors declare no conflict of interest.

This work was supported by JSPS KAKENHI Grant Number JP16K10587.

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