P0582Tertiary lymphoid structure: a therapeutic target and predictor of anti-TNF response in Inflammatory Bowel Diseases

Abstract Background Tertiary lymphoid structures (TLS) in inflammatory bowel disease (IBD) have traditionally been regarded as secondary structures accompanying chronic inflammation. We hypothesize that TLS are crucial components in the pathological environment that promote ulcer formation and that biological agents function by disrupting this TLS-dependent niche. Our goal is to examine the relationship between inflammatory cytokines—targets for biological agents—and TLS; assess the effect of anti-TNF therapy on TLS; and evaluate the potential to predict anti-TNF therapy effectiveness using biopsy TLS indicators. Methods To address the limitation of mucosal biopsies that do not cover the entire ulcerative niche, Xenium analysis was performed on full-thickness intestinal segments from surgical resection specimens, including four untreated cases and four cases treated with TNF inhibitors. Additionally, from 849 surgical cases collected between 2014 and 2019, 105 cases were selected—82 untreated and 23 treated with anti-TNF monotherapy. In a propensity-score-matched immunohistochemistry cohort (1:3 ratio, n = 60), the presence of TLS, follicular dendritic cells, and high endothelial venules were quantitatively assessed. Furthermore, in public biopsy data (CD and ulcerative colitis; UC), prediction of TNF inhibitor responsiveness was performed using pre-treatment TLS indicators. Results (1) The number of TLS was linked to clinical and histological activity indices, showing TLS burden as a measurable marker of the ulcerative niche. (2) In untreated samples, TNF-positive cells targeted by TNF inhibitors were sparse within the mucosal lamina propria and were mostly concentrated within the TLS. (3) In cases treated with anti-TNF therapy, there was a notable reduction in TNF-positive cells and CXCL13-positive follicular dendritic cells (FDCs) within the TLS, along with changes such as an increase in M2 macrophages inside the TLS. (4) In cases that did not respond to TNF inhibitors, TLS persisted despite FDC depletion, with CXCL13-positive Tfh cells still present, indicating a Tfh-dependent compensatory niche. (5) TLS status at pre-treatment biopsy was a reliable predictor of response to TNF inhibitors in both CD and UC (CD: AUC 0.762; UC: AUC 0.867). Conclusion TLS is more than just an indicator; it is an ulcerative niche. By interfering with CXCL13⁺ follicular dendritic cell networks, anti-TNF therapy disrupts TLS-supporting niches and reduces TLS burden. Conversely, Tfh-derived CXCL13 may play a distinct role in promoting local tolerance. The TLS index in pre-treatment biopsy specimens proved useful for anti-TNF stratification in CD/UC. Conflict of interest: Dr. Kodama, Makoto: No conflict of interest Nagase, Yoshihiro: No conflict of interest Okano, Soh: No conflict of interest Yamamoto, Kouhei: No conflict of interest Furukawa, Asuka: No conflict of interest Yamamoto, Kurara: No conflict of interest Miyata, Ryota: No conflict of interest Abe, Keiko: No conflict of interest Ohteki, Toshiaki: No conflict of interest Makishima, Makoto: No conflict of interest