{
  "abstract": "Background Current IBD treatment paradigms assume that greater mucosal immune infiltration warrants more aggressive immunosuppression. We identified a striking paradox: the molecularly least immune-infiltrated IBD subtype demonstrated the highest infliximab response rate. We aimed to formally characterise this ‘Cold IBD’ phenotype and determine whether mucosal immune burden predicts anti-TNF response.Methods Immune cell infiltration was estimated using a 13-cell-type signature-based deconvolution applied to batch-corrected transcriptomes from 616 colonic biopsies across four GEO cohorts (GSE75214, GSE179285, GSE16879, GSE36807). Unsupervised consensus clustering (k=3) identified three molecular subtypes: Metabolic-Absorptive (C1), Hypoxia-Metabolic (C2), and Inflammatory-EMT (C3). A Total Immune Burden Score (TIBS) was derived as the mean z-scored expression of all immune signatures per sample. TIBS was correlated with infliximab response in pre-treatment biopsies from GSE16879 (n=61) by ROC analysis and point-biserial correlations per cell type.Results C2 exhibited the lowest TIBS (-0.424±0.332) versus C3 (0.490±0.409) and C1 (0.002±0.420). Paradoxically, C2, the immunologically coldest subtype, achieved the highest infliximab response rate (92%), while the most immune-infiltrated subtype, C3, responded in only 29% of cases ( IDDF2026-ABS-0228 Figure 1. Immune burden by molecular subtype).Pre-treatment TIBS significantly predicted infliximab non-response (responders: -0.015±0.320 vs non-responders: 0.413±0.385; t=-4.67, p=0.00002; AUC=0.805) (IDDF2026-ABS-0228 Figure 2. Immune cell profile per subtype). At the optimal threshold, 87.5% of high-TIBS patients were non-responders versus 32.4% of low-TIBS patients (IDDF2026-ABS-0228 Figure 3. Immune cell correlation with infliximab non-response). Individual cell-type analysis identified monocytes (r=0.624, p<0.001) (IDDF2026-ABS-0228 Figure 4. Immune burden responders vs non-responders pre-treatment) and neutrophils (r=0.596, p<0.001) (IDDF2026-ABS-0228 Figure 5. ROC immune burden predicts infliximab non-response) as the strongest predictors of non-response, surpassing macrophages, plasma cells, and all T cell subsets and implicating innate myeloid dominance, not adaptive immunity, as the primary driver of treatment resistance (IDDF2026-ABS-0228 Figure 6. Immune burden projected onto UMAP).Conclusions Mucosal immune burden paradoxically predicts anti-TNF failure rather than treatment need in IBD. Patients with the lowest immune infiltration respond best to infliximab, while pan-immune activated patients, driven principally by monocyte and neutrophil infiltration, are primary non-responders. These findings invert the current treat-to-target paradigm and suggest that pre-treatment immune profiling should guide biological therapy selection in IBD.Abstract IDDF2026-ABS-0228 Figure 1Abstract IDDF2026-ABS-0228 Figure 2Abstract IDDF2026-ABS-0228 Figure 3Abstract IDDF2026-ABS-0228 Figure 4Abstract IDDF2026-ABS-0228 Figure 5Abstract IDDF2026-ABS-0228 Figure 6",
  "authors": [
    {
      "affiliations": [
        "New York Medical College, United States"
      ],
      "name": "Jeril Lasington"
    },
    {
      "affiliations": [
        "Rutgers University, United States"
      ],
      "name": "Lawin Steve Mathew Lasington"
    }
  ],
  "title": "IDDF2026-ABS-0228 Hot gut, cold response: dissecting the mucosal immune architecture of anti-tnf resistance in IBD",
  "uid": "a1b863eb-db48-5e01-b04f-3fd971eb02a5"
}