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TLR9 Mediated Tumor-Stroma Interactions in Human Papilloma Virus (HPV)-Positive Head and Neck Squamous Cell Carcinoma Up-Regulate PD-L1 and PD-L2

Baruah, P; Bullenkamp, J; Wilson, P; Lee, M; Kaski, JC; Dumitriu, IE (2019) TLR9 Mediated Tumor-Stroma Interactions in Human Papilloma Virus (HPV)-Positive Head and Neck Squamous Cell Carcinoma Up-Regulate PD-L1 and PD-L2. Frontiers in Immunology, 10. p. 1644. ISSN 1664-3224 https://doi.org/10.3389/fimmu.2019.01644
SGUL Authors: Dumitriu, Ingrid Elena

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Abstract

Background: The co-inhibitory receptor PD-1 is expressed in many tumors including head and neck squamous cell carcinoma (HNSCC) and is an important immunotherapy target. However, the role of PD-1 ligands, PD-L1, and particularly PD-L2, in the tumor-stromal cell interactions that cause a tumor-permissive environment in HNSCC is not completely understood and is the focus of our study. Methods: Expression of PD-L1 and PD-L2 was analyzed by immunohistochemistry in situ in HNSCC tumor tissue. Co-cultures were established between stromal cells (fibroblasts and macrophages) and human papilloma virus (HPV)-positive and HPV-negative HNSCC cell lines (HNSCCs) and PD-1 ligands expression was analyzed using flow cytometry. Results: PD-L1 and PD-L2 were expressed both in tumor cells and stroma in HNSCC tissue in situ. In vitro, basal expression of PD-L1 and PD-L2 was low in HNSCCs and high on fibroblasts and macrophages. Interestingly, HPV-positive but not HPV-negative HNSCCs increased the expression of both PD-1 ligands on fibroblasts upon co-culture. This effect was not observed with macrophages. Conversely, both fibroblasts and macrophages increased PD-1 ligands on HPV-positive HNSCCs, whilst this was not observed in HPV-negative HNSCCs. Crucially, we demonstrate that up-regulation of PD-L1 and PD-L2 on fibroblasts by HPV-positive HNSCCs is mediated via TLR9. Conclusions: This work demonstrates in an in vitro model that HPV-positive HNSCCs regulate PD-L1/2 expression on fibroblasts via TLR9. This may open novel avenues to modulate immune checkpoint regulator PD-1 and its ligands by targeting TLR9.

Item Type: Article
Additional Information: Copyright © 2019 Baruah, Bullenkamp, Wilson, Lee, Kaski and Dumitriu. 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.
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Frontiers in Immunology
ISSN: 1664-3224
Dates:
DateEvent
16 July 2019Published
2 July 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
SRG/12/059Royal College of Surgeons of Edinburghhttp://dx.doi.org/10.13039/501100000692
SRG/10/033Royal College of Surgeons of Edinburghhttp://dx.doi.org/10.13039/501100000692
PG/10/50/28434British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PG/13/24/30115British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PG/14/18/30724British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PG/17/15/32845British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
URI: http://sgultest.da.ulcc.ac.uk/id/eprint/111008
Publisher's version: https://doi.org/10.3389/fimmu.2019.01644

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