Inhibition of ERO1a and IDO1 improves dendritic cell infiltration into pancreatic ductal adenocarcinoma

Apple Hui Min Tay; Riccardo Cinotti; Newman Sui Kwan Sze; Andreas Lundqvist

doi:10.3389/fimmu.2023.1264012

Inhibition of ERO1a and IDO1 improves dendritic cell infiltration into pancreatic ductal adenocarcinoma

Front Immunol. 2023 Dec 22:14:1264012. doi: 10.3389/fimmu.2023.1264012. eCollection 2023.

Authors

Apple Hui Min Tay^{1

2}, Riccardo Cinotti², Newman Sui Kwan Sze^{1

3}, Andreas Lundqvist²

Affiliations

¹ School of Biological Science, Nanyang Technological University, Singapore, Singapore.
² Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
³ Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, St. Catharines, ON, Canada.

Abstract

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and treatment resistant cancers. Due to its desmoplastic and hypoxic nature along with an abundance of myeloid cell infiltration and scarce T cell infiltration, PDAC is considered a cold tumor.

Methods: Here we sought to investigate myeloid cell infiltration and composition in PDAC spheroids by targeting the hypoxia-associated pathways endoplasmic reticulum oxidoreductase 1 alpha (ERO1a) and indoleamine 2,3-dioxygenase 1 (IDO1). Using MiaPaCa2 spheroids with hypoxic core, we assessed the roles of ERO1a and IDO1 inhibition in modulating monocyte infiltration and differentiation, followed by characterizing immunomodulatory factors secreted using LC-MS/MS.

Results: Inhibition of ERO1a and IDO1 significantly improved monocyte infiltration and differentiation into dendritic cells. LC-MS/MS analysis of the PDAC spheroid secretome identified downregulation of hypoxia and PDAC pathways, and upregulation of antigen presentation pathways upon inhibition of ERO1a and IDO1. Furthermore, immunomodulatory factors involved in immune infiltration and migration including interleukin-8, lymphocyte cytosolic protein 1, and transgelin-2, were upregulated upon inhibition of ERO1a and IDO1.

Discussion: Collectively, our results show that inhibition of ERO1a and IDO1 modulates the tumor microenvironment associated with improved monocyte infiltration and differentiation into dendritic cells to potentially influence therapeutic responses in patients with PDAC.

Keywords: ERO1a; IDO1; PDAC; dendritic cell; myeloid cell compartment; secretome; spheroid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Pancreatic Ductal*
Chromatography, Liquid
Dendritic Cells
Humans
Hypoxia
Pancreatic Neoplasms*
Tandem Mass Spectrometry
Tumor Microenvironment

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from The Swedish Cancer Society (#CAN2018/451 and #21 1524 Pj), The Cancer Research Foundations of Radiumhemmet (#181183 and #211253), Karolinska Institutet and Robert Lundberg Memorial Foundation (#2023-01691).