Prediction of steroid demand in the treatment of patients with ulcerative colitis by immunohistochemical analysis of the mucosal microenvironment and immune checkpoint: role of macrophages and regulatory markers in disease severity

• Published in: Pathology international Vol. 69; no. 5; pp. 260 - 271
• Main Authors: Tsuda, Shingo, Carreras, Joaquim, Kikuti, Yara Y, Nakae, Hirohiko, Dekiden‐Monma, Makiko, Imai, Jin, Tsuruya, Kota, Nakamura, Jun, Tsukune, Yoko, Uchida, Tetsufumi, Matsushima, Masashi, Roncador, Giovanna, Suzuki, Takayoshi, Nakamura, Naoya, Mine, Tetsuya
• Format: Journal Article
• Language: English
• Published: Australia Wiley Subscription Services, Inc 01.05.2019
• Subjects: Adult; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Biomarkers; BTLA; BTLA protein; C-Reactive Protein - metabolism; CD11c antigen; CD16 antigen; CD163; CD163 antigen; CD3 antigen; CD4 antigen; CD8 antigen; Colitis, Ulcerative - immunology; Colitis, Ulcerative - pathology; Colitis, Ulcerative - therapy; Colon; Correlation analysis; Female; Forkhead Transcription Factors - metabolism; FOXP3; Foxp3 protein; Gene expression; GSEA; Homeostasis; Humans; Immune checkpoint; immune homeostasis; Immunohistochemistry; Immunomodulation - physiology; Infectious diseases; Inflammatory bowel disease; Macrophages; Macrophages - immunology; Macrophages - pathology; Male; Markers; microenvironment biomarkers and immune checkpoint; Middle Aged; Mucosal immunity; Mucous Membrane - immunology; Mucous Membrane - pathology; Pathogenesis; PD‐1; prognosis; Programmed Cell Death 1 Receptor - metabolism; Receptors, Cell Surface - metabolism; Receptors, Immunologic - metabolism; Receptors, Tumor Necrosis Factor, Member 14 - metabolism; Serum Amyloid P-Component - metabolism; Steroids; Steroids - therapeutic use; TNFRSF14; Ulcerative colitis; CD163; macrophages; BTLA; GSEA; TNFRSF14; microenvironment biomarkers and immune checkpoint; immune homeostasis; FOXP3; PD-1; prognosis; Ulcerative colitis
• ISSN: 1320-5463; 1440-1827
• DOI: 10.1111/pin.12794

We aimed to characterize the mucosal immune microenvironment and immune checkpoint of Ulcerative colitis (UC) by immunohistochemistry with correlation to prognosis: requirement of second‐line steroid‐therapy within the 2‐years after diagnosis (SR). A series of 72 cases included 56 UC, 43 non‐SR (with first‐line treatment 5‐ASA) and 13 SR, 11 infectious colitis and 5 normal colonic biopsies. Normal mucosa was characterized by low infiltrates but high BTLA and TNFRSF14. Compared to normal, UC had increased pan‐immune‐markers of CD3, CD8, FOXP3, PD‐1, CD68, CD16, CD163, PTX3 and CD11C but had decreased BTLA (P < 0.05); by GSEA analysis comparable results were found in an independent UC gene‐expression‐data set (GSE38713). Compared to infectious, UC had higher CD4, CD8, PTX3 and CD11C but lower BTLA (P < 0.05). Compared to non‐SR, SR had lower FOXP3 + Tregs (Odds‐Ratio = 0.114, P = 0.002), PD‐1 (OR = 0.176, P = 0.002) and CD163/CD68 M2‐ratio (OR, 0.019, P = 0.019) but higher CD68 + pan‐macrophages (OR = 6.034, P = 0.002). Higher Baron endoscopic and Geboes histologic disease activity scores also correlated with SR. In summary, UC was characterized by increased pan‐immune‐markers, normal TNFRSF14 and low BTLA. SR had increased CD68 + pan‐macrophages but lower immune inhibitors of FOXP3 + Tregs, PD‐1 and CD163/CD68 M2‐macrophage ratio. In conclusion, alterations of the immune homeostasis mechanisms are relevant in the UC pathogenesis and steroid‐requiring situation.