University of Oulu

Sieviläinen M, Saavalainen J, Adnan-Awad S, Salo T and Al-Samadi A (2022) IDO1 Inhibition Reduces Immune Cell Exclusion Through Inducing Cell Migration While PD-1 Blockage Increases IL-6 and -8 Secretion From T Cells in Head and Neck Cancer. Front. Immunol. 13:812822. doi: 10.3389/fimmu.2022.812822

IDO1 inhibition reduces immune cell exclusion through inducing cell migration while PD-1 blockage increases IL-6 and -8 secretion from T cells in head and neck cancer

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Author: Sieviläinen, Meri1,2; Saavalainen, Jordan1,3; Adnan-Awad, Shady4,5;
Organizations: 1Department of Oral and Maxillofacial Diseases, Clinicum, University of Helsinki, Helsinki, Finland
2Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
3School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
4Clinical Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt
5Hematology Research Unit, Department of Hematology, University of Helsinki and Helsinki University Central Hospital Comprehensive Cancer Center, Helsinki, Finland
6Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland
7Medical Research Center, Oulu University Hospital, Oulu, Finland
8Department of Pathology, Helsinki University Hospital (HUS), Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 5.9 MB)
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Language: English
Published: Frontiers Media, 2022
Publish Date: 2022-09-26


Background: Immune checkpoint inhibitors (ICIs), primarily anti-PD-1, are currently used to treat patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, only a minority of patients benefit from these costly therapies. Therefore, there is an unmet need to better understand the effect of ICIs on immune effector cells. This study aimed to investigate the effect of a PD-1 antibody and an IDO1 inhibitor on different lymphocyte populations (NK, CD4⁺, and CD8⁺ T cells) in term of migration, cytotoxicity, and cytokine release in the presence of HNSCC cells.

Methods: Using a microfluidic chip, we injected HSC-3 cells (an oral tongue squamous cell carcinoma cell line) embedded in a human tumor-derived matrix “myogel/fibrin” together with NK, CD4⁺, and CD8⁺ T cells in separate channels. The two channels were connected with microchannels. The PD-1 antibody nivolumab and IDO1 inhibitor epacadostat were added to the microfluidic chips. Lymphocyte migration and cytotoxicity were examined under fluorescent microscopy and cytokine release was measured using a FirePlex Human Discovery Cytokines Immunoassay.

Results: Epacadostat significantly increased the migration and infiltration of NK and CD4⁺ T cells, but not CD8⁺ T cells, towards the cancer cells. Nivolumab did not exhibit a similar effect. While CD8⁺ T cells alone showed near to no migration, adding CD4⁺ T cells enhanced migration towards the cancer cells. There was a mild nonsignificant increase in apoptosis of HSC-3 cells after adding epacadostat to lymphocytes. In contrast, HSC-3 proliferation was not affected by lymphocytes regardless of ICIs. Nivolumab significantly increased release of MIP1-α, IL-6, and IL-8 from NK, CD4⁺, and CD8⁺ T cells, respectively.

Conclusions: This study revealed that each subpopulation of lymphocytes respond differently to ICIs. We also revealed the subpopulation of lymphocytes responsible for the increases in specific serum cytokines after ICI treatment.

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Series: Frontiers in immunology
ISSN: 1664-3224
ISSN-E: 1664-3224
ISSN-L: 1664-3224
Volume: 13
Article number: 812822
DOI: 10.3389/fimmu.2022.812822
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
1182 Biochemistry, cell and molecular biology
Funding: MS was financially supported by a fellowship from the Doctoral Programme in Oral Sciences. The project was funded by the Niilo Helander Foundation, the Maja och Lisa Selander Foundation, Suomen Naishammaslääkäriseura, the Cancer Society of Finland, the Sigrid Juselius Foundation, the Finnish Dental Society Apollonia, the Jane and Aatos Erkko Foundation, and Helsinki University Central hospital research funds. The microfluidic solutions and devices were provided by Probiont Oy, Helsinki, Finland as direct support to this study.
Copyright information: © 2022 Sieviläinen, Saavalainen, Adnan-Awad, Salo and Al-Samadi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.