Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression

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dc.contributor.author Guo, Yanxia
dc.contributor.author Walsh, Alice M
dc.contributor.author Canavan, Mary
dc.contributor.author Wechalekar, Mihir
dc.contributor.author Cole, Suzanne
dc.contributor.author Yin, Xuefeng
dc.contributor.author Scott, Brittney
dc.contributor.author Loza, Mathew
dc.contributor.author Orr, Carl
dc.contributor.author McGarry, Trudy
dc.contributor.author Bombardieri, Michele
dc.contributor.author Humby, Frances
dc.contributor.author Proudman, Susanna
dc.contributor.author Pitzalis, Costantino
dc.contributor.author Smith, Malcolm Douglas
dc.contributor.author Friedman, Joshua R
dc.contributor.author Anderson, Ian
dc.contributor.author Madakamutil, Loui
dc.contributor.author Veale, Douglas J
dc.contributor.author Fearon, Ursula
dc.contributor.author Nagpal, Sunil
dc.date.accessioned 2018-10-04T23:55:07Z
dc.date.available 2018-10-04T23:55:07Z
dc.date.issued 2018-02-28
dc.description This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. en_US
dc.description.abstract Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception. en_US
dc.description.sponsorship This study was supported by funding from Johnson & Johnson. The funder provided support in the form of funding for data generation and salaries for authors [YG, AMW, SC, XY, BS, ML, JRF, IA, LM, SN], but did not have any additional role in the study design, decision to publish, or preparation of the manuscript. en_US
dc.identifier.citation Guo, Y., Walsh, A.M., Canavan, M., Wechalekar, M.D., Cole, S., Yin, X. et al., (2018). Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression. PLoS ONE, 13(2): e0192704. en_US
dc.identifier.doi https://doi.org/10.1371/journal.pone.0192704 en_US
dc.identifier.issn 1932-6203
dc.identifier.uri http://hdl.handle.net/2328/38367
dc.language.iso en en_US
dc.publisher Public Library of Science en_US
dc.rights © 2018 Guo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. en_US
dc.rights.holder © 2018 Guo et al. en_US
dc.rights.license CC-BY
dc.title Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression en_US
dc.type Article en
local.contributor.authorOrcidLookup Wechalekar, Mihir: https://orcid.org/0000-0001-6668-9638 en_US
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