Background/Purpose: Exhaustion can occur after prolonged activation of T cells limiting their immunosurveillance function leading to cancer emergence. Among the exhaustion markers expressed on T cells are PD-1 and TIGIT. While exhaustion has been extensively studied in cancer where it is the target of immune checkpoint inhibitors it is less investigated in the field of Immune mediated inflammatory diseases (IMIDs). In an era where PD-1 agonists like peresolimab are trialed in rheumatoid arthritis, better understanding of the role of exhaustion in IMIDs is crucial. This work aims to assess the level of circulating exhausted CD4 and CD8 T cells in patients with IMID and prospectively assess how these cell subsets at baseline might impact response to anti-TNF.

Methods: We have included 25 patients with rheumatoid arthritis (RA), 22 patients with spondyloarthritis (SPA) and 20 patients with Sjogren disease (SjD). T-cell exhaustion has been assessed by flow-cytometry on fresh whole blood. Exhausted T cells were defined as double positive PD-1+ TIGIT+ among circulating CD8 and CD4 T cells. Patients with RA and SA were evaluated at baseline and 3 months after anti-TNF initiation. IFNα2a, IFN-β, IFNγ, IFNλ1, and IP-10 were measured in sera in all the patients at baseline using MSD technology. Response to anti-TNF treatment was defined by treatment maintenance on drug at 12 months post initiation. Patients who switched treatment for side effects were excluded. Associations between exhausted T-cells and categorical or continuous variables were performed by logistic regression/Fisher exact test or Mann–Whitney test, respectively.

Results: The median level of exhausted CD4 T cells (T₄ex) was higher in SjD (15,4%) compared to RA (11,5%), SPA (9,26%) and to healthy volunteers. Median CD8+ exhausted T cells (T₈ex) were higher in SjD patients (23.20%) and RA patients (24.00%) compared to HV (18%) and SPA patients (16,2%). There was no association between T₄ex or T₈ex and disease activity scores or demographic variables. Interestingly, in SjD, T₄ex were positively associated to serum IgG levels (r=0.698, p< 0.001), IFN-γ levels (R=0.635, p=0.017) and IP-10 levels (R=0.612, p=0.005).

At baseline before treatment, T4ex among CD4⁺ T cells were significantly higher in anti-TNF-α responders vs non responders (median: 9.89% [7.64;13.95] vs. 6.07% [5.34;6.14] respectively, p=0.003) (Figure 1). Finally, we observed a significant increase of exhausted CD8+ and CD4+ T cells 3 months after anti-TNF treatment in RA and SPA treatment compared to baseline (figure 2). This increase was not significantly different between anti-TNF responders and non-responders.

Conclusion: Exhausted T-cells are differentially enriched between IMIDs. Sjögren patients showed the most consistent increased in T₄ex and T₈ex,T4ex being associated with IgG levels, IFNg and IP-10. High baseline levels of T₄ex are associated with better response to anti-TNF. After 3 months of anti-TNF treatment, all RA and SPA patients display an increase of T₄ex and T₈ex regardless their response to treatment. Further work is needed to evaluate if a high level of T4ex could be a biomarker predictive of response to agonists of TIGIT or of PD1 like peresolimab.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/exhausted-t-cells-are-increased-in-autoimmune-diseases-and-predict-response-to-anti-tnf-in-ra-and-spa-patients/