Journal Article

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

Cole, Suzanne, Scott, Brittney, McGarry, Trudy, Madakamutil, Loui, Friedman, Joshua R., Walsh, Alice M., Pitzalis, Costantino, Wechalekar, Mihir D., Guo, Yanxia, Veale, Douglas J., Humby, Frances, Fearon, Ursula, Nagpal, Sunil, Orr, Carl, Proudman, Susanna M., Loza, Mathew, Bombardieri, Michele, Anderson, Ian, Canavan, Mary, Smith, Malcolm D., Yin, Xuefeng

2018

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Antibodies / Antigens / Apoptosis / Arthralgia / Arthritis / Arthritis, Rheumatoid - pathology / Autoantibodies / Autoimmune diseases / Biology and Life Sciences / Cancer / Care and treatment / CD4 antigen / CD8 antigen / Cellular proteins / Cytotoxicity / Development and progression / Disease / Disease Progression / Down-Regulation / Female / Funding / Gene expression / Genetic aspects / Health aspects / Hospitals / Humans / Immune checkpoint / Immune checkpoint inhibitors / Immune response / Immunohistochemistry / Immunology / Inflammation / Interception / Kinases / Ligands / Lymphocytes / Lymphocytes T / Male / Medicine and Health Sciences / Monoclonal antibodies / Nivolumab / Osteoarthritis / Patients / PD-1 protein / PD-L1 protein / Programmed Cell Death 1 Receptor - metabolism / Repatriation / Research and Analysis Methods / Rheumatic diseases / Rheumatoid arthritis / Rheumatology / Signaling / Software / Supervision / Synovial Membrane - metabolism / Synovial Membrane - pathology / Synovium / T cell receptors / Targeted cancer therapy / Tissues / University colleges / Walsh, Mary