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

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.

Rheumatic Syndromes Associated With Immune Checkpoint Inhibitors: A Single‐Center Cohort of Sixty‐One Patients

“…We also observed that in several patients with inflammatory arthritis, inflammatory symptoms persisted after discontinuation of ICI therapy, which is largely unique to Rh‐irAEs . Patients with RA have exhibited increased expression of PD‐1 in synovial tissue , suggesting one potential mechanistic pathway whereby ICIs may induce disease flares or reveal preclinical RA .…”

A single administration of human adipose tissue-derived mesenchymal stromal cells (MSC) induces durable and sustained long-term regulation of inflammatory response in experimental colitis

“…Interestingly, in this study we found that MSC treatment led to increased PD-1 expression in T reg after short-and long-term evaluation, which may contribute to the protective effects of MSC on gut inflammation. The interaction of these surface molecules has been reported as important factor that attenuates the inflammatory response in autoimmune diseases [63]. Conversely, GITR is constitutively expressed by T reg and upon exposure to alloantigens [62].…”

Dendritic cells, T cells and their interaction in rheumatoid arthritis

“…Briefly, PD-1 is expressed by activated T and B cells [45]. Of interest, transcripts of the co-inhibitory PD-L1 ligand are highly expressed in RA synovium, but expression of PD-L1 protein appears to be blocked by serum soluble (s)PD-L1, which is present at high levels in seropositive RA, thereby downregulating the PD-1/PD-L1 inhibitory signalling axis [47]. Of interest, transcripts of the co-inhibitory PD-L1 ligand are highly expressed in RA synovium, but expression of PD-L1 protein appears to be blocked by serum soluble (s)PD-L1, which is present at high levels in seropositive RA, thereby downregulating the PD-1/PD-L1 inhibitory signalling axis [47].…”