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Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy

Martin et al. Cell (2019)
Mass cytometry validates a 4-module cell subset score identified by single cell sequencing associated with resistance to anti-TNF therapy in patients with ileal Crohn's disease.
Mass cytometry validates a 4-module cell subset score identified by single cell sequencing associated with resistance to anti-TNF therapy in patients with ileal Crohn’s disease.

Antibodies against tumor necrosis factor (anti-TNF) are ineffective in 20-30% of patients with ileal Crohn’s disease. To determine the underlying reasons, Martin et al. at the Icahn School of Medicine conducted paired immune profiling on ileal tissues resected from 11 patients. Based on the high sensitivity of single-cell sequencing for rare subpopulations, the researchers identified a unique module, “GIMATS” (IgG plasma cells, Inflammatory Mononuclear phagocytes, Activated T cells, and Stromal cells), with highly correlated frequencies across inflamed ileums. The immunophenotype of GIMATS was further confirmed by mass cytometry and multiplexed immunohistochemical staining.

Interestingly, in four independent cohorts of ileal Crohn’s disease (n = 441), patients who had a high GIMATS score prior to starting an anti-TNF regimen were more likely to fail to achieve clinical remission at least 6 months later (p = 0.005; n = 71), suggesting the GIMATS score can be used to predict response to anti-TNF therapy at baseline to avoid a second biopsy. These results also indicated that combining anti-TNF with drugs targeting the cell subsets that comprise the GIMATS score may overcome the anti-TNF resistance in patients with high GIMATS scores.

Data suggest the GIMATS score can be used to predict response to anti-TNF therapy at baseline to avoid a second biopsy.

Additionally, traditional inflammation testing panels are unable to distinguish between ileal Crohn’s disease patients with high and low GIMATS module scores, indicating that the GIMATS score provides information about immunotherapy response that is not conveyed by conventional biomarkers.

More recent analysis by Kosoy et al. in 2021 (see our highlight here) have profiled the impact of anti-TNF therapy on immune subset frequencies and found distinct changes in B cell and T cell subsets. To date, a immune-based score has not been incorporated into clinical treatment decisions for ileal Crohn’s disease.

Reference citation: Martin JC, Chang C, Boschetti G, Ungaro R, Giri M, Grout JA, Gettler K, Chuang LS, Nayar S, Greenstein AJ, Dubinsky M, Walker L, Leader A, Fine JS, Whitehurst CE, Mbow ML, Kugathasan S, Denson LA, Hyams JS, Friedman JR, Desai PT, Ko HM, Laface I, Akturk G, Schadt EE, Salmon H, Gnjatic S, Rahman AH, Merad M, Cho JH, Kenigsberg E. Single-Cell Analysis of Crohn’s Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy. Cell. 2019 Sep 5;178(6):1493-1508.e20. doi: 10.1016/j.cell.2019.08.008

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