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

Date Published: February 28, 2018

Publisher: Public Library of Science

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


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.

Partial Text

Immune check-point blockade has shown unprecedented superiority to prior therapies in cancer treatment as demonstrated by significantly prolonged survival of patients given anti-cytotoxic T lymphocyte-associated antigen-4 (anti-CTLA-4, Ipilumimab) [1], anti-programmed death-1 (anti-PD-1, Pembrolizumab and Nivolumab) [2, 3], or anti-PD-L1 (anti-PD-Ligand 1, Atezolizumab) [4] antibodies. Immune modulatory activities of these novel drugs are essential for the robust clinical efficacy observed in cancer patients. Given that these co-inhibitory molecules are part of the immune homeostatic mechanisms that dampen overt immune activation [5, 6], it is natural to predict immunotherapy to be a double-edged sword that activates immune cells to attack cancer cells but also harbors the potential to unleash self-antigen reactive T cells, thus leading to inflammatory and autoimmune diseases. In fact, studies have revealed immune-related adverse events (irAE) in a subset of patients treated with Ipilimumab, Nivolumab, or Pembrolizumab or a combination of anti-CTLA-4 and anti-PD-1 therapeutics. The checkpoint blockade adverse events include arthralgia [7], inflammatory arthritis (IA) [8], tenosynovitis [9], colitis [10] and psoriasis [11]. A comparative study of checkpoint blockade-mediated IA and the naturally occurring cases of the related disease during rheumatoid arthritis (RA) evolution may provide insight into the mechanism(s) of disease development and progression and uncover therapeutic pathways for the treatment and prevention.

Herein, by utilizing gene signatures derived from human metastatic renal carcinoma patients following an antagonistic anti-PD-1 antibody treatment [19], we have identified PD-1 pathway as a common molecular mechanism linking Nivolumab-mediated IA and the naturally occurring disease during RA progression. The major findings are: 1) the expression of PDCD1, CD274 and PDCD1LG2 is elevated in synovial tissues at various stages of RA disease progression; 2) PD-1 is expressed on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells; 3) Nivolumab-responsive genes in TME are enriched in synovial biopsies; 4) serum sPD1 is elevated in ACPA+ early RA patients and, 5) PD-L1 protein is not available in the early RA synovium for agonistic interaction with PD-1.




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