Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.
Authors
Guo, YanxiaWalsh, Alice M
Canavan, Mary
Wechalekar, Mihir D
Cole, Suzanne
Yin, Xuefeng
Scott, Brittney
Loza, Mathew
Orr, Carl
McGarry, Trudy
Bombardieri, Michele
Humby, Frances
Proudman, Susanna M
Pitzalis, Costantino
Smith, Malcolm D
Friedman, Joshua R
Anderson, Ian
Madakamutil, Loui
Veale, Douglas J
Fearon, Ursula
Nagpal, Sunil
Issue Date
2018MeSH
Arthritis, RheumatoidDisease Progression
Down-Regulation
Female
Humans
Male
Programmed Cell Death 1 Receptor
Synovial Membrane
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Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression. 2018, 13 (2):e0192704 PLoS ONEPublisher
PLoS OneJournal
PloS oneDOI
10.1371/journal.pone.0192704PubMed ID
29489833Abstract
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.Item Type
ArticleLanguage
enISSN
1932-6203ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0192704
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