THU0025 Florid synovitis after pd1 antagonist therapy is characterised by a marked absence of pd1+ infiltrating t cells
Authors: W. Murray-Brown, T. Wilsdon, H. Weedon, S. Proudman, M.D. Smith, J. Walker, M.D. Wechalekar
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Although immunological blockade of checkpoint inhibitors (CIs) for cancer therapy is known to be associated with exacerbated inflammation recapitulating many features of autoimmunity<sup>1</sup>, including synovitis resembling rheumatoid arthritis (RA)<sup>2</sup>, no reports have investigated cellular infiltrates in synovial tissue (ST) of these patients. Here we provide the first report on ST cell infiltration, in particular PD1 expressing T cells, after a PD1 inhibitor-induced (Nivolumab) immune related adverse event (irAE) and severe synovitis. <h3>Objectives</h3> To characterise ST cellular infiltration in PD1 inhibitor induced arthritis with particular reference to PD1 positive T cells and compare these changes with active early RA ST. <h3>Methods</h3> Arthroscopic ST biopsies, parallel synovial fluid (SF) and PBMCs were collected from a DMARD-naïve nivolumab-treated small cell lung cancer (SCLC) patient with severe peripheral inflammatory polyarthritis (negative RF and ACPA; no axial or extra-articular irAE); 3 DMARD-naïve patients with seropositive early RA (&lt;12 months duration; fulfilling 2010 ACR/EULAR criteria) were used as comparators. Serial sections from fresh-frozen ST blocks were stained with H and E, CD3, CD45RO, CD55 and CD68 and semi-quantitatively scored as described<sup>3</sup>. ST, SF and PBMC cell suspensions were stained with Zombie UV (BioLegend), CD45RO, PD1, CD3, ICOS, CD8, CD4, CD20 (all BD) prior to flow cytometry. Cells were gated on live, singlet, lymphocytes, CD3+ and CD4+ T cells, and CD20+ and CD8+ T cells were excluded from endpoint PD1+, ICOS+ and CD45RO+analysis. <h3>Results</h3> CD68 +macrophage, CD20+ B cell and CD3+ T cell and CD45RO+memory T cell infiltration in IC-irAE was comparable to RA ST on semi-quantitative scoring, while TNF; staining was markedly elevated in CI-irAE compared to RA (CI-irAE-TNF; 4, RA-TNF; 2). Flow cytometry identified a striking absence of PD1+ ICOS+ CD4+T cells in IC-irAE SCLC in all compartments (CI-irAE: ST; 0.06, SF; 0.01, PBMCs; 0.00) compared to RA (RA: ST mean and SEM; 22.13±3.63: SF; 45.95±1.85: and to a lesser extent in PBMCs; 0.41±0.13: n=3 for each), despite comparable CD4 +T cell frequency in each compartment (frequency of CD3 +cells, CI-irAE: ST; 57.8, SF; 64.7, PBMCs; 38.2, RA: ST; 45.9±15.3, SF; 49.5±11.2, PBMCs; 62.2±13.8, figure 1). Figure 1 PD-1 +ICOS + T cells are absent in CI-irAE. Showing the PD-1 +ICOS + frequency of CD4 +T cells gated on live, singlet, lymphocytes, and CD3+, CD20- and CD8-cells. (RA: ST mean and SEM; 22. 13±3.63: SF; 45.95±1.85 n=3 for each, CI-irAE: ST; 0.06, SF; 0.01, PBMCs; 0.00, n=1 for each). <h3>Conclusions</h3> While ST infiltration in CI-irAE SCLC recapitulates many features of RA histopathology, PD1 expression principally distinguishes RA from irAE ST T-cell infiltration. Despite abundant CD4 and CD45RO memory T cell infiltration in CI-irAE comparable with RA, we found a conspicuous absence of PD1 positive T-cells. Further research is needed to fully understand the nature of reduced PD1 expression in this setting and the source of elevated TNF, which could shed light on the pathogenesis of CI-irAE and guide CI-irAE management. <h3>References</h3> [1] van der Vlist, et al. Immune checkpoints and rheumatic diseases: what can cancer immunotherapy teach us?Nat Rev Rheumatol2016. [2] Naidoo, J. et al. Inflammatory Arthritis: A Newly Recognized Adverse Event of Immune Checkpoint Blockade. Oncologist2017. [3] Tak, P. P. et al. Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum. 1997. <h3>Disclosure of Interest</h3> None declared