Cell-centred meta-analysis reveals baseline predictors of anti-TNFα non-response in biopsy and blood of patients with IBD

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Abstract

Objective

Although anti-tumour necrosis factor alpha (anti-TNFα) therapies represent a major breakthrough in IBD therapy, their cost–benefit ratio is hampered by an overall 30% non-response rate, adverse side effects and high costs. Thus, finding predictive biomarkers of non-response prior to commencing anti-TNFα therapy is of high value.

Design

We analysed publicly available whole-genome expression profiles of colon biopsies obtained from multiple cohorts of patients with IBD using a combined computational deconvolution—meta-analysis paradigm which allows to estimate immune cell contribution to the measured expression and capture differential regulatory programmes otherwise masked due to variation in cellular composition. Insights from this in silico approach were experimentally validated in biopsies and blood samples of three independent test cohorts.

Results

We found the proportion of plasma cells as a robust pretreatment biomarker of non-response to therapy, which we validated in two independent cohorts of immune-stained colon biopsies, where a plasma cellular score from inflamed biopsies was predictive of non-response with an area under the curve (AUC) of 82%. Meta-analysis of the cell proportion-adjusted gene expression data suggested that an increase in inflammatory macrophages in anti-TNFα non-responding individuals is associated with the upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) –axes. Blood gene expression analysis of an independent cohort, identified TREM-1 downregulation in non-responders at baseline, which was predictive of response with an AUC of 94%.

Conclusions

Our study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFα therapy prior to initiation of treatment. Moreover, it suggests that mechanism-driven novel drugs for non-responders should be developed.

Related collections

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Author and article information

Journal

Journal ID (nlm-ta): Gut

Journal ID (iso-abbrev): Gut

Journal ID (hwp): gutjnl

Journal ID (publisher-id): gut

Title: Gut

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0017-5749

ISSN (Electronic): 1468-3288

Publication date (Print): April 2019

Publication date (Electronic): 4 April 2018

Volume: 68

Issue: 4

Pages: 604-614

Affiliations

[1 ] departmentFaculty of Medicine , Technion-Israel Institute of Technology , Haifa, Israel

[2 ] CytoReason

[3 ] departmentDepartment of Gastroenterology , Rambam Health Care Campus , Haifa, Israel

[4 ] departmentDivision of Biomedical Informatics Research, Department of Medicine , Stanford University , Palo Alto, California, USA

[5 ] departmentStanford Institute for Immunity Transplantation and Infection, Department of Medicine , Stanford University , Palo Alto, California, USA

[6 ] departmentDepartment of Gastroenterology and Liver Diseases, IBD Center , Tel Aviv Sourasky Medical Center , Tel Aviv, Israel

[7 ] departmentSackler Faculty of Medicine , Tel Aviv University , Tel Aviv, Israel

[8 ] departmentDivision of Gastroenterology , Rabin Medical Center , Petah Tikva, Israel

[9 ] departmentDepartment of Pathology , Rambam Health Care Campus , Haifa, Israel

Author notes

[Correspondence to ] Yehuda Chowers, Division of Gastroenterology, Rambam Health Care Campus, Haifa, Israel; y_chowers@ 123456rambam.health.gov.il , Purvesh Khatri, Department of Medicine, Stanford University, Palo Alto, California, USA; pkhatri@ 123456stanford.edu and Shai S Shen-Orr, Faculty of Medicine, Technion, Haifa 32000, Israel; shenorr@ 123456technion.ac.il

Article

Publisher ID: gutjnl-2017-315494

DOI: 10.1136/gutjnl-2017-315494

PMC ID: 6580771

PubMed ID: 29618496

SO-VID: 69a1b95c-c82e-40ce-9546-140ae26ad486

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/