P085 Tc17 cells with a distinct immune signature do not correlate with response to therapy with ustekinumab or TNF antibodies in active Crohn’s Disease

Abstract

Abstract Background IL-17 producing CD8+ T cells (Tc17) expressing a specific immune signature (CD6high, CD39, CD69, PD-1, CD27low) were shown to be associated with active Crohn’s Disease (CD) and inform flare free survival. Here, we addressed the question whether Tc17 cells and their signature also correlate with response of CD patients to therapies with antibodies targeting TNFα or IL-12/23. Methods Peripheral blood mononuclear cells were longitudinally collected from CD patients prior to and up to 35 weeks after initiation of therapy with either TNF antibodies or ustekinumab and CD8+ T cells were analyzed by flow cytometry. Results were correlated with clinical outcomes. Results We analyzed dynamic changes during treatment in blood samples of 36 CD patients initiating anti-TNF (n = 14) or ustekinumab therapy (N = 22). Baseline Tc17 frequencies differed between ustekinumab and anti-TNF treatment groups, with significantly higher frequencies in the ustekinumab group. This may be due to differences in the baseline patient characteristics; while ustekinumab treated patients were all previously treated with anti-TNF-antibodies, most of the anti-TNF treated patients were naïve to biologics. Indeed, Tc17 frequencies increased during anti-TNF treatment, while Tc17 frequencies were reduced at follow up in the ustekinumab group. However, Tc17 frequencies in the peripheral blood at baseline did not correlate with response to either therapy, nor did the frequencies of Tc17 cells expressing Tc17 signature proteins. The expression of Tc17 signature proteins by IL-17A producing CD8+ T cells did not change significantly during follow up, suggesting that the Tc17 signature was preserved during anti-TNF and ustekinumab therapy. We did not observe major changes in the production of pro-inflammatory cytokines by Tc17 cells during therapy. Conclusion Our data suggest that despite playing a pathogenic role in CD, Tc17 cells with a distinct immune signature do not directly correlate with response to therapy with anti-TNF agents or ustekinumab. However, anti-TNF therapy may skew CD8 T cell differentiation towards a Tc17 phenotype, which may have an impact on long term disease outcomes and should be investigated further.